Substituted peptidylamine calcium channel blockers

ABSTRACT

The present invention provides compounds that block calcium channels having the Formula I shown below. ##STR1## The present invention also provides methods of using the compounds of Formula I to treat stroke, cerebral ischemia, head trauma, or epilepsy and to pharmaceutical compositions that contain the compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of PCT/US 98/10838, filed May 28, 1998,and U.S. Ser. No. 60/052,191, filed Jul. 10, 1997, and U.S. Ser. No.60/048,252, filed May 30, 1997.

FIELD OF THE INVENTION

The present invention relates to compounds that act to block calciumchannels; methods of using the compounds to treat stroke, cerebralischemia, pain, head trauma or epilepsy; and to pharmaceuticalcompositions that contain the compounds of the present invention.

BACKGROUND OF THE INVENTION

The entry of excessive amounts of calcium ions into neurons following anischemic episode or other neuronal trauma has been well documented.Uncontrolled high concentrations of calcium in neurons initiates acascade of biochemical events that disrupts normal cellular processes.Among these events are the activation of proteases and lipases,breakdown of neuronal membranes and the formation of free radicals,which may ultimately lead to cell death. Several types of calciumchannels have been discovered and called the L, N, P, Q, R, and T types.Each type possesses distinct structural features, functional propertiesand cellular/subcellular distributions. Type selective calcium channelblockers have been identified. For example, SNX-111 has been shown to bea selective N-type calcium channel blocker and has demonstrated activityin a number of models of ischemia and pain (Bowersox S. S., et al., DrugNews and Perspective, 1994:7:261-268 and references cited therein). Thecompounds of the present invention are calcium channel blockers that canblock N-type calcium channels and can be used to treat stroke, pain,cerebral ischemia, head trauma, and epilepsy.

SUMMARY OF THE INVENTION

The present invention provides compounds having the Formula I ##STR2##wherein * denotes a first chiral center when R³ and R⁴ are different;

@ denotes a second chiral center;

R¹ and R² are independently hydrogen, C₁ -C₈ alkyl, C₃ -C₇ cycloalkyl,

C₃ -C₈ substituted alkyl, C₁ -C₆ alkoxy, hydroxy, C₃ -C₆heterocycloalkyl,

C₃ -C₇ cycloalkenyl, C₃ -C₇ substituted, cycloalkenyl, C₃ -C₇substituted

cycloalkyl, --(CH₂)_(n) -aryl, (CH₂)_(n) -substituted aryl, C₂ -C₈alkenyl, ##STR3## C₂ -C₈ substituted alkenyl, --CH₂ --COC₁ -C₆ alkyl,--CH₂ --COH,

--(CH₂)_(n) -heteroaryl, --(CH₂)_(n) -substituted heteroaryl,

--(CH₂)_(n) --C₃ -C₇ heterocycle, --(CH₂)_(n) -substituted C₃ -C₇heterocycle,

--(CH₂)_(n) -cycloalkyl, --(CH₂)_(n) -substituted cycloalkyl, or R¹ andR² may be taken together to form a 5- to 7-membered ring which maycontain heteroatoms, provided that R¹ and R² are not both hydrogen;

R³, R⁵, and R⁶ are independently hydrogen or C₁ -C₈ alkyl;

R⁴ is C₁ -C₈ alkyl,

--(CH₂)_(n) C₃ -C₇ cycloalkyl,

--(CH₂)_(n) C₃ -C₇ substituted cycloalkyl, or

--(CH₂)_(n) phenyl;

Y is --(CH₂)_(n) --, --O(CH₂)_(n) --, --(CH₂)_(n) O--, --N(R³)(CH₂)_(n)--, --(CH₂)_(n) N(R³)--,

--S(CH₂)_(n) --, --(CH₂)_(n) S--, --C═C--, or --C.tbd.C--;

Z is aryl, substituted aryl, heteroaryl, substituted heteroaryl, C₃ -C₇cycloalkyl, substituted C₃ -C₇ cycloalkyl, or C₁ -C₈ alkyl;

X is heterocycle, substituted heterocycle,

--NH(CH₂)_(n) NR³ R⁵,

--NH(CH₂)_(n) heteroaryl,

--NH(CH₂)_(n) substituted heteroaryl,

--NH(CH₂)_(n) NH(CH₂)_(n) phenyl,

--NH(CH₂)_(n) NH(CH₂)_(n) --OH,

--NH-heterocycle-CH₂ phenyl, ##STR4## --NH(CH₂)_(n) -heterocycloalkyl,--OC₁ -C₆ alkyl, ##STR5## --NH(CH₂)_(n) heterocycle, --NH(CH₂)_(n)substituted heterocycle;

--OR³, --NHR³, --NR³ R⁵, wherein in addition to the definitions of R³and R⁵ above, R³ and R⁵ can together with the nitrogen atom form a ringhaving from 3 to 7 atoms;

each n is 0 to 5, and the pharmaceutically acceptable salts, esters,amides and prodrugs thereof.

In a preferred embodiment of the compound of Formula I, R¹ is methyl.

In another preferred embodiment of the compounds of Formula I, R³, R⁵,and R⁶ are hydrogen.

In another preferred embodiment of the compounds of Formula I, ##STR6##or --O-tert-butyl.

In another preferred embodiment of the compounds of Formula I, ##STR7##

In another preferred embodiment of the compounds of Formula I, Z isphenyl.

In another preferred embodiment of the compounds of Formula I, R¹ ismethyl, R³, R⁵, and R⁶ are hydrogen, R⁴ is isobutyl, ##STR8## Y is--OCH₂ --, and Z is phenyl.

In another preferred embodiment of the compounds of Formula I, R³ ishydrogen and R² is C₁ -C₈ alkyl, substituted cyclohexyl, cyclohexyl,cyclohexenyl, --CH₂ -phenyl, --CH₂ -substituted phenyl, --CH₂-cyclohexyl, ##STR9## R² and R³ taken together along with the nitrogenatom form a ring having the structure ##STR10##

In another preferred embodiment of the compounds of Formula I, R³ isisobutyl, and R⁴ is hydrogen.

In another preferred embodiment of the compounds of Formula I, R⁵ and R⁶are hydrogen.

In another preferred embodiment of the compounds of Formula I, R² is C₁-C₈ alkyl, cyclohexyl, substituted cyclohexyl, --CH₂ -phenyl, or --CH₂-substituted phenyl.

In another preferred embodiment of the compounds of Formula I, ##STR11##--O-tert-butyl, ##STR12##

In another more preferred embodiment of the compounds of Formula I,

R¹ is methyl; and

R² is C₁ -C₈ alkyl, substituted cyclohexyl, cyclohexyl, cyclohexenyl,--CH₂ -phenyl, --CH₂ -substituted phenyl, --CH₂ -cyclohexyl, C₁ -C₈alkenyl, --CH₂ -pyridyl, ##STR13## wherein m is 3, 4, 5, or 6; R³, R⁵,and R⁶ are hydrogen;

R⁴ is isobutyl; ##STR14## or --O-tert-butyl; ##STR15## Z is phenyl.

In another more preferred embodiment of the compounds of Formula I,

Y is --O--CH₂ -- or ##STR16## Z is phenyl; ##STR17## --O-tert-butyl##STR18## R⁴ and R⁵ are hydrogen; R³ is isobutyl;

R¹ is methyl; and

R² is C₁ -C₈ alkyl, --(CH₂)_(n) substituted phenyl, or cyclohexyl.

In a most preferred embodiment of the present invention, the compoundsare:

2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;

2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amide;

2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin4-ylcarbamoyl)-ethyl]-amide;

2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-but-2-enylamino)-pentanoylamino]-propionicacid tert-butyl ester;

3-(4-Benzyloxy-phenyl)-2-[2-(4-tert-butyl-benzylamino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester;

2-(2-Benzylamino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(3,3-Dimethyl-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-Diethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-tert-Butyl-cyclohexyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(4-methyl-cyclohexyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Isobutyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-methylamino-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

3-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[ethyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-butyric acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Cyclohex-2-enyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Cyclohex-2-enylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-(Benzyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide; and

2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.

In another most preferred embodiment of the present invention, thecompounds are:

2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(2-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(2-Hydroxycyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(Isoprop-2-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(N-methyl-piperidin-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(N-methyl-piperidin-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(Pyran-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-[(Pyran-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-Morpholine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbarnoyl-ethyl]-amide;

2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl)]-amide;

2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Bromo-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(3-Chloro-benzyl)-methyl-amino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Hydroxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(2-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(2-Hydroxycyclohexyl-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1carbamoyl-ethyl)]-amide;

2-(Isoprop-2-yl)-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[N-methyl-piperidin-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(N-methyl-piperidin-4-yl)-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(Pyran-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(Pyran-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-Morpholine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl)]-amide;

2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl -pentanoic acid[1-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Bromo-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Hydroxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(2-Metboxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-(2-Hydroxycyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl]-amide;

2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl]-2-oxo-ethyl-amide;

2-[(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-[(Isoprop-2-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-Morpholine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl-1-tert-butylcarbamoyl-ethyl]-amide;

2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-thiomorpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propyl-carbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxypiperidinylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-y-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidine-1-yl-ethylcarbamoyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxy-piperinylcarbamoyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-(2-aminoethyl)pyridinecarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(thiomorpholinecarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-aminopropan-1-ol carbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxymethylbutan-1-ol)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;and

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin- 1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-thiomorpholin4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propyl-carbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxypiperidinylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidine-1-yl-ethylcarbamoyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxy-piperinylcarbamoyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-(2-aminoethyl)pyridinecarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(thiomorpholinecarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-aminopropan-1-ol carbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxymethylbutan-1-ol)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;and

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amide.

Also provided is a pharmaceutical composition comprising a compound ofFormula I.

Also provided is a method of blocking calcium channels, the methodcomprising administering to a patient in need of calcium channelblocking, a therapeutically effective amount of a compound of Formula Ito block calcium channels.

In a preferred embodiment of the method, the calcium channels are N-typecalcium channels.

In another embodiment, the present invention provides a method ofblocking N-type calcium channels, the method comprising administering toa patient in need of N-type calcium channel blocking a therapeuticallyeffective amount of a compound of Formula I effective to block N-typecalcium channels.

The invention also provides a method of treating stroke, the methodcomprising administering to a patient having a stroke a therapeuticallyeffective amount of a compound of Formula I.

The invention also provides a method of preventing a stroke, the methodcomprising administering to a patient at risk of having a stroke atherapeutically effective amount of a compound of Formula I.

The invention also provides a method of treating cerebral ischemia, themethod comprising administering to a patient having cerebral ischemia atherapeutically effective amount of a compound of Formula I.

The invention also provides a method of treating head trauma, the methodcomprising administering to a patient having head trauma atherapeutically effective amount of a compound of Formula I.

Also provided is a method of treating epilepsy, the method comprisingadministering to a patient having epilepsy a therapeutically effectiveamount of a compound of Formula I.

Also provided is a method of treating pain, the method comprisingadministering to a patient having pain a therapeutically effectiveamount of a compound Formula I.

Also provided are the compounds:

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Bromo-benzyl)-methyl-amino-]4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Hydroxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin-4-ylmethyl-amino)-pentanoic acid[2-(4-bezyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,S*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoylamino]-propionicacid tert-butyl ester;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-[R*,R*,(RS)]]-2-[(2-Hydroxy-1-methyl-ethyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(1H-pyrrol-2-ylmethyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-(Furan-2-ylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[2-(cyclohexylmethyl-amino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester;

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-(2-isopropylamino-4-methyl-pentanoylamino)-propionicacid tert-butyl ester;

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-(2-cyclohexylamino-4-methyl-pentanoylamino)-propionicacid tert-butyl ester;

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-butylamino)-pentanoylamino]-propionicacid tert-butyl ester;

[S-(R*,R*)]-({1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-amino)-aceticacid ethyl ester;

[S-(R*,R*)]-2-[(3 -Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]4-Methyl-2-piperidin-1-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-Ethylamino4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin-3-ylmethyl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-{2-[methyl-(3-methyl-butyl)-amino]-acetylamino}-propionamide;

[S-[R*,R*,(RS)]]-2-(sec-Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

(S)-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbarnoyl-ethyl]-2-(3-methyl-butylamino)-isobutyramide;

[S-(R*,R*)]-4-Methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-(Isopropyl-methyl-amino)4-methyl-pentanioc acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbarnoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

2-(Isopropyl-methyl-amino)-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

2-[(4-tertButyl-benzyl-)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

[S, (R*,R*)]-4-Methyl-2-piperidin-1-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S, (R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amidemonohydrochloride;

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl }-amide;

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;

[S-(R*,R*)]-2-[(3-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(2-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(4-methylsulfanyl-benzyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamnoyl]-ethyl}-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin- 1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-2-(sopropyl-methyl-amino)-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]4-methyl-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl- 1'-yl-2-oxo-ethyl]-amide;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl- 1'-yl-2-oxo-ethyl]-amide;

2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;

[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-phenethyl-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;

[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclohexyl-ethyl)-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;

[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclopentyl-ethyl)-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;

[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclohexyl-ethyl)-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]amide;

4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-(Isopropyl-methyl-amino)-4-methyl-pentanioc acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

4-Methyl-2-[methyl-(3-methyl-butyl-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

2-(Isopropyl-methyl-amino)-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;

2-[(4-tertButyl-benzyl-)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbanoyl)-ethyl]-amide;and

2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having the Formula I ##STR19##wherein * denotes a first chiral center when R³ and R⁴ are different;

@ denotes a second chiral center;

R¹ and R² are independently hydrogen, C₁ -C₈ alkyl, C₃ -C₇ cycloalkyl,

C₃ -C₈ substituted alkyl, C₁ -C₆ alkoxy, hydroxy, C₃ -C₆heterocycloalkyl,

C₃ -C₇ cycloalkenyl, C₃ -C₇ substituted, cycloalkenyl, C₃ -C₇substituted cycloalkyl, --(CH₂)_(n) -aryl, (CH₂)_(n) -substituted aryl,C₂ -C₈ alkenyl,

C₂ -C₈ substituted alkenyl, ##STR20## --(CH₂)_(n) -heteroaryl,--(CH₂)_(n) -substituted heteroaryl,

--(CH₂)_(n) --C₃ -C₇ heterocycle, --(CH₂)_(n) -substituted C₃ -C₇heterocycle, --(CH₂)_(n) -cycloalkyl, --(CH₂)_(n) -substitutedcycloalkyl, or R¹ and R² may be taken together to form a 5- to7-membered ring which may contain heteroatoms, provided that R¹ and R²are not both hydrogen;

R³, R⁵, and R⁶ are independently hydrogen or C₁ -C₈ alkyl;

R⁴ is C₁ -C₈ alkyl,

--(CH₂)_(n) C₃ -C₇ cycloalkyl,

--(CH₂)_(n) C₃ -C₇ substituted cycloalkyl, or

--(CH₂)_(n) phenyl;

Y is --(CH₂)_(n) --, --O(CH₂)_(n) --, --(CH₂)_(n) O--, --N(R³)(CH₂)_(n)--, --(CH₂)_(n) N(R³)--, --S(CH₂)_(n) --, --(CH₂)_(n) S--, --C═C--, or--C.tbd.C--;

Z is aryl, substituted aryl, heteroaryl, substituted heteroaryl, C₃ -C₇cycloalkyl, substituted C₃ -C₇ cycloalkyl, or C₁ -C₈ alkyl;

X is heterocycle, substituted heterocycle,

--NH(CH₂)_(n) NR³ R⁵,

--NH(CH₂)_(n) heteroaryl,

--NH(CH₂)_(n) substituted heteroaryl,

--NH(CH₂)_(n) NH(CH₂)_(n) phenyl,

--NH(CH₂)_(n) NH(CH₂)_(n) --OH,

--NH-heterocycle-CH₂ phenyl, ##STR21## --NH(CH₂)_(n) -heterocycloalkyl,--OC₁ -C₆ alkyl, ##STR22## --NH(CH₂)_(n) heterocycle, --NH(CH₂)_(n)substituted heterocycle;

--OR³, --NHR³, --NR³ R⁵, wherein in addition to the definitions of R³and R⁵ above, R³ and R⁵ can together with the nitrogen atom form a ringhaving from 3 to 7 atoms;

each n is 0 to 5, and the pharmaceutically acceptable salts, esters,amides, and prodrugs thereof.

Two chiral centers that can have either R or S configurations aredesignated above in Formula I by the symbols "*" and "@". It is intendedthat the present invention cover compounds having the S,S; R,R; S,R; orR,S configurations and mixtures thereof.

The term "alkyl" means a straight or branched chain hydrocarbon.Representative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term "alkoxy" means an alkyl group attached to an oxygen atom.Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy.

The term "halogen" includes chlorine, fluorine, bromine, and iodine.

The term "alkenyl" means a branched or straight chain hydrocarbon havingone or more carbon-carbon double bond.

The term "aryl" means an aromatic hydrocarbon. Representative examplesof aryl groups include phenyl and naphthyl.

The term "heteroatom" includes oxygen, nitrogen, and sulfur.

The term "heteroaryl" means an aryl group wherein one or more carbonatom of the aromatic hydrocarbon has been replaced with a heteroatom.Examples of heteroaryl radicals include, but are not limited to,pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl,pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.

The term "cycloalkyl" means a cyclic hydrocarbon. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The symbol "--" means a bond.

The term "patient" means all animals including humans. Examples ofpatients include humans, cows, dogs, cats, goats, sheep, and pigs.

The term "substituted" means that the base organic radical has one ormore substituents. For example, substituted cyclohexyl means acyclohexyl radical that has one or more substituents. Substituentsinclude, but are not limited to, halogen, C₁ -C₈ alkyl, --CN, CF₃,--NO₂, --NH₂, --NHC₁ -C₈ alkyl, --N(C₁ -C₈ alkyl)₂, --SC 1-C₈ alkyl,--OC₁ -C₈ alkyl, and --OH. Particularly preferred substituents include,but are not limited to tert-butyl, methyl, chlorine, fluorine, bromine,--OCH₃, --OCH₂ CH₃, --OH, and --N(CH₃)₂.

The term "cycloalkenyl" means a cycloalkyl group having at least onecarbon-carbon double bond. Examples of cycloalkenyl groups includecyclopentene, cyclobutene, and cyclohexene.

The term "heterocycle" means a cycloalkyl group wherein one or morecarbon atom is replaced with a heteroatom. Examples of heterocyclesinclude, but are not limited to, pyrrolidinyl, piperidinyl, andpiperazinyl.

Those skilled in the art are easily able to identify patients having astroke or at risk of having a stroke; cerebral ischemia; head trauma; orepilepsy. For example, patients who are at risk of having a strokeinclude, but is not limited to patients having hypertension orundergoing major surgery.

A therapeutically effective amount is an amount of a compound of FormulaI, that when administered to a patient, ameliorates a symptom of thedisease.

The compounds of the present invention can be administered to a patienteither alone or a part of a pharmaceutical composition. The compositionscan be administered to patients either orally, rectally, parenterally(intravenously, intramuscularly, or subcutaneously), intracisternally,intravaginally, intraperitoneally, intravesically, locally (powders,ointments, or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The term "pharmaceutically acceptable salts, esters, amides, andprodrugs" as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term "salts" refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the presentinvention. These salts can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Representative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium and amine cations including, butnot limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, S. M. Berge, et al., "PharmaceuticalSalts," J. Pharm. Sci., 1977;66:1-19 which is incorporated herein byreference.)

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁ -C₆ alkyl esters wherein thealkyl group is a straight or branched chain. Acceptable esters alsoinclude C₅ -C₇ cycloalkyl esters as well as arylalkyl esters such as,but not limited to benzyl. C₁ -C₄ alkyl esters are preferred. Esters ofthe compounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁ -C₆ alkyl amines and secondary C₁ -C₆ dialkyl amines wherein thealkyl groups are straight or branched chain. In the case of secondaryamines the amine may also be in the form of a 5- or 6-memberedheterocycle containing one nitrogen atom. Amides derived from ammonia,C₁ -C₃ alkyl primary amines, and C₁ -C₂ dialkyl secondary amines arepreferred. Amides of the compounds of the invention may be preparedaccording to conventional methods.

The term "prodrug" refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The compounds of the present invention can exist in differentstereoisomeric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisomeric forms of thecompounds, as well as mixtures thereof including racemic mixtures, formpart of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 1,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 100 mg per kilogram of bodyweight per day is preferable. The specific dosage used, however, canvary. For example, the dosage can depended on a numbers of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell known to those skilled in the art.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as throughmetabolism.

The examples presented below are intended to illustrate particularembodiments of the invention and are not intended to limit the scope ofthe specification, including the claims, in any way.

The following abbreviations are used throughout this application:

    ______________________________________                                        Pr       Propyl                                                               Et       Ethyl                                                                HBTU     2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uranium                          hexafluorophosphate                                                  Bz or Bn Benzyl                                                               TFA      Trifluoroacetic acid                                                 APCI     Atmospheric pressure chemical ionization                             NMR      Nuclear magnetic resonance                                           TLC      Thin layer chromatography                                            HPLC     High pressure liquid chromatography                                  DMF      Dimethyl formamide                                                   EtOAC    Ethyl acetate                                                        EtOH     Ethanol                                                              MS       Mass spectrum                                                        DCM      Dichloromethane                                                      Et.sub.3 N                                                                             Triethyl amine                                                       THF      Tetrahydrofuran                                                      IR       Infrared                                                             OAc      Acetate                                                              bu       Butyl                                                                iso-pr   Iso-propyl                                                           FMOC     9-Fluorenylmethyloxycarbonyl                                         BOC      Tertiary butyloxycarbonyl                                            ______________________________________                                    

EXAMPLES

Synthesis

Scheme IV below illustrates the preparation ofN,N-disubstituted-leucine-(OBz)-tyrosine amides (IV) using polymersupported resins in synthesis. The preparation ofTyrosine-(O-Benzyl)-amides (intermediates 1) are illustrated in SchemeI. The preparation of N,N-dialkyl leucine acids (intermediates II) areillustrated in Schemes II and III.

Step I: The Preparation of Tyrosine-(OBenzyl)-Amides (I) ##STR23## StepII: The Preparation of N,N-dialkyl Leucine Acids (II)

Schemes II and III illustrate general methods of preparing N,N-dialkylLeucine acids (II). ##STR24## Step III: The preparation ofN,N-disubstituted-Leucine-(OBz)-Tyrosine amides (IV) ##STR25##

N,N-Dialkyl leucine acid [II, 0.1 mmol, 1 equivalent (eq.)] was placedin a 2 dram vial and morpholine resin (IIIc, 150 mg, 3.6 mmol/g, 5.4eq.) was added. The mixture was treated with dichloromethane (1.5 mL)and isobutylchloroformate (18 μL, 1.4 eq.). The vial was capped andshaken for 30 minutes. The (O-benzyl)-tyrosine amide (I, 0.1 mmol, 1eq.) was added as a solution in dichloromethane (1 mL), and the mixturewas shaken for 2 hours. Isocyanate resin (IIIb, 100 mg, 1.5 mmol/g, 1.5eq.) and amine resin (IIIa, 100 mg, 1.5 mmol/g, 1.5 eq.) were added, andthe mixture was shaken for 2 hours. The solids were filtered awaythrough a plug of glass wool in a pipette. The solids were rinsed with 1mL dichloromethane, and the combined solvent volume was evaporated undera stream of N₂. The product was analyzed by APCI mass spectrometry, ¹ HNMR, TLC (SiO₂), and HPLC.

Example 1 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The Preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Ia)##STR26## Step i: N-Boc-O-Benzyl-tyrosine (20.0 g, 53.9 mmol) wasdissolved in DMF (270 mL) and treated with diisopropylethylamine (19 mL,108 mmol), tert-butylamine (5.7 mL. 53.9 mmol), and HBTU (13.9 g, 53.9mmol). The reaction was stirred for 15 minutes and then diluted withEtOAc (1 L), washed with saturated bicarbonate solution (2×1 L) andbrine (1 L), dried over Na₂ SO₄ and concentrated to give 22.1 g (92%) of(S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acidtert-butyl ester.

MS: 428 (M+1 for C₂₅ H₃₄ N₂ O₄); TLC: SiO₂, R_(f) 0.49 (10% MeOH/CH₂Cl₂).

Step ii:(S)-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acidtert-butyl ester (6.0 g, 14.1 mmol) was dissolved in CH₂ Cl₂ (28 mL) andtreated with trifluoroacetic acid (28 mL). The reaction was stirred for20 minutes and then concentrated. The residue was diluted with EtOAc(300 mL), washed with saturated bicarbonate solution (2×300 mL) andbrine (300 mL), dried over Na₂ SO₄, and concentrated to give 4.2 g (91%)of Ia.

MS: 328 (M+1 for C₂₀ H₂₆ N₂ O₃); TLC: SiO₂, R_(f) 0.43 (10% MeOH/CH₂Cl₂).

Step 2: The Preparation of (S)-2-(Dimethyl-amino)-4-methyl-pentanoicacid (IIa) ##STR27##

(S)-2-Amino-4-methyl-pentanoic acid (10.42 g, 80 mmol) was dissolved inH₂ O (120 mL) and treated with formaldehyde (80 mL, 37% solution), andRaney Nickel (2 g), and stirred for 21 hours. The solution wasconcentrated to a solid, dissolved in hot EtOH, boiled with charcoal,and filtered through Celite. The solution was allowed to cool. Acetonewas added, and the solution was placed in the refrigerator. The solutionwas filtered and the crystals were washed with acetone to give 9.7 g(77%) of IIa.

MS: 160 (M+1 for C₈ H₁₇ N₁ O₂); TLC SiO₂, R_(f) 0.04 (12% MeOH/CH₂Cl.sub.₂).

Step 3: The Preparation of Polymer-supported Resins (III)

The Preparation of the Polymer-supported Tris(2-aminoethyl)Amine (IIIa)

A suspension of Merrifield resin (Fluka, 50 g, 1.7 mmol Cl/g resin, 85mmol) in DMF (500 mL) was treated with tris(2-aminoethyl)amine (50 mL,342 mmol). The resulting mixture was shaken at 65° C. for 6 hours underN₂ atmosphere. After cooling to room temperature, the resin was filteredand washed successively with MeOH, DMF, Et₃ N, MeOH, DCM, Et₃ N, MeOH,DCM, MeOH, DCM, and MeOH. The resulting amine resin was dried at 45-50°C., 20 mmHg for 24 hours, and stored in tightly sealed bottles. Calc'd:N, 8.02; Cl, 0.00. Found: N, 5.96; Cl, 0.42 (indicates approx. 25%cross-linking). A small sample reacted with excess 3,4-dichlorophenylisocyanate in DCM indicates a quenching capacity of 3.18 mmol/g resin,consistent with three-quarters of the N content in the amine resin(IIIa). Calc'd: N, 6.51; Cl, 14.15. Found: N, 6.25; Cl, 13.99.

The Preparation of the Polymer-Supported Isocyanate (IIIb)

A suspension of aminomethyl resin (Fluka, 1.1 mmol N/g resin, 15 g, 16.5mmol) in DCM (150 mL) was treated with Et₃ N (11.5 mL, 83 mmol) andtriphosgene (3.25 g, 2 mmol equivalents of phosgene) and shaken 5 hoursat room temperature. The resulting isocyanate resin was filtered andwashed DCM (2×200 mL), CHCl₃ (2×200 mL), Et₂ O (1×200 mL), THF (1×200mL), Et₂ O (1×200 mL), THF (1×200 mL), and Et₂ O (1×200 mL). The resinwas then dried at 35-40° C., 25 mmHg for 24 hours. Yield (15 g of IIIb)IR (KBr) 2260 (N═C═O). Calc'd: C,; N,; Found: C, 87.04; N, 1.45.

The Preparation of the Polymer-Supported Morpholine (IIIc)

A suspension of Merrifield resin (Fluka, Ronkankoma, New York, 20 g, 4.3mmol Cl/g resin, 86 mmol) in DMF (100 mL) was treated with morpholine(20 mL, 229 mmol). The resulting mixture was shaken at 65° C. for 6hours under N₂ atmosphere, then allowed to stand at room temperature 24hours. After cooling to room temperature, the resin was filtered andwashed successively with MeOH, DMF, MeOH, Et₃ N, DCM, MeOH, Et₃ N, DCM,MeOH, EtOAc, and Hexanes. The resulting N-methylmorpholine resin (IIIc)was dried at 45-50° C., 20 mmHg for 48 hours, and stored in tightlysealed bottles. Calc'd. N, 4.83; Cl, 0.00. Found: N, 4.98; Cl, 0.21.

Step 4: Example 1: [S-(R*,R*)]-2-Dimethylamino-4methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide ##STR28##

N,N-Dimethyl-L-leucine (IIa, 15.9 mg, 0.1 mmol) and morpholine resin(IIIc, 150 mg, 0.54 mmol) were treated with CH₂ Cl₂ (1.5 mL) andisobutylchloroformate (18 μL, 0.14 mmol). The vial was capped and shakenfor 30 minutes. O-Benzyl-L-tyrosine-t-butyl-amide (Ia, 32.6 mg, 0.1mmol) was added as a solution in dichloromethane (1 mL), and the mixturewas shaken for 2 hours. Isocyanate resin (IIIb, 100 mg, 0.15 mmol) andamine resin (IIIa, 100 mg, 0.15 mmol) were added, and the mixture wasshaken for 2 hours. The solids were filtered away through a plug ofglass wool in a pipette. The solids were rinsed with 1 mLdichloromethane, and the combined solvent volume was evaporated under astream of N₂ to give 41 mg (88%) of the title compound (Example 1).

MS: 469 (M+1 for C₂₈ H₄₁ N₃ O₃); TLC: SiO₂, R_(f) 0.56 (10% MeOH/CH₂Cl₂).

Example 2 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide

Step 1: The preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib):Ib is made in accordance in the process of Ia, except piperidine wasused instead of t-butylamine.

Step 2: Example 2: [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide is madein accordance with the process of Example 1, except(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib)was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 481 (M+1 for C₂₉ H₄₁ N₃ O₃); sticky solid; TLC: R_(f) 0.52 (10%MeOH/CH₂ Cl₂).

Example 3 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide

Step 1: The preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide(Ic): Ic is made in accordance in the process of Ia, except2-piperidinyl 1-ethylamine was used instead of t-butylamine.

Step 2: Example 3: [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide(Ic) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 524 (M+1for C₃₁ H₄₆ N₄ O₃); sticky solid; TLC: R_(f) 0.16 (10%MeOH/CH₂ Cl₂).

Example 4 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide

Step 1: The preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id): Id is made in accordance in the process of Ia, except4-benzyl-piperazine was used instead of t-butylamine.

Step 2: Example 4: [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 572 (M+1 for C₃₅ H₄₆ N₄ O₃); sticky solid; TLC: R_(f) 0.55 (10%MeOH/CH₂ Cl₂).

Example 5 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amide

Step 1.(S)-2-Amino-3-(4-henzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie): Ie is made in accordance with the process of Ia, except4-amino-1-benzyl-piperidine was used instead of t-butylamine.

Step 2. Example 5: [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 586 (M+1 for C₃₆ H4₈ N₄ O₃); sticky solid; TLC: R_(f) 0.44 (10%MeOW/CH₂ Cl₂).

Example 6 [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

Step 1.(S)-2-Amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If): If is made in accordance with the process of Ia, except4-methylpiperazine was used instead of t-butylamine.

Step 2. Example 44: [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 495 (M+1 for C₂₉ H₄₂ N₄ O₃); sticky solid; TLC: R_(f) 0.66 (10%MeOH/CH₂ Cl₂).

Example 7[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The preparation of(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid IIb)##STR29## Step i: N-Methyl-O-benzyl-L-leucine p-tosylate salt (4.01 g,9.84 mmol) was dissolved in CH₂ Cl₂ (50 mL) and treated withisovaleraldehyde (1.06 mL, 9.84 mmol). The reaction was stirred at roomtemperature for 30 minutes and then cooled to 0° C. Sodiumtriacetoxyborohydride (3.13 g, 14.8 mmol) was added, and the reactionwas allowed to warm to room temperature and stir overnight. The reactionwas diluted with CH₂ Cl₂ (400 mL). The organic layer was washed twicewith saturated bicarbonate solution (2×400 mL), once with brine (400mL), and then dried over Na₂ SO₄. The solution was filtered,concentrated, and the crude material chromatographed on silica geleluting with 10% EtOAc/hexanes to give 2.86 g (90%) of(S)4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid benzylester as a pale oil.

MS: 306 (M+1 for C₁₉ H₃₁ N₁ O₂); TLC: SiO₂, R_(f) 0.33 (10%EtOAc/hexanes).

Step ii: (S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acidbenzyl ester (0.89 g, 2.89 mmol) was dissolved in THF (75 mL) and shakenwith 20% Pd/C (0.1 g) under an H₂ atmosphere (52 psi) for 30 minutes.The catalyst was removed by filtration through a pad of Celite, and thesolution was concentrated to give 0.50 g (81%) of IIb as a white solid.

MS: 216 (M+1 for C₁₂ H₂₅ N₁ O₂); TLC: SiO₂, R_(f) 0.32 (10% MeOH/CH₂Cl₂).

Step 2: Example 6:[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 1, exceptN-(3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine.

MS: 525 (M+1 for C₃₂ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 0.53 (10%MeOH/CH₂ Cl₂).

Example 8

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide is made inaccordance with the process of Example 1, exceptN-(3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib)was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 537 (M+1 for C₃₃ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 0.53 (10%MeOH/CH₂ Cl₂).

Example 9

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide(Ic) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 580 (M+1 for C₃₅ H₅₄ N₄ O₃); sticky solid; TLC: R_(f) 0.29 (10%MeOH/CH₂ Cl₂).

Example 10

[S-(R*,R*)]4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 628 (M+1 for C₃₉ H₅₄ N₄ O₃); sticky solid; TLC: R_(f) 0.52 (10%MeOH/CH₂ Cl₂).

Example 11

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 642 (M+1 for C₄₀ H₅₆ N₄ O₃); sticky solid; TLC: R_(f) 0.45 (10%MeOH/CH₂ Cl₂).

Example 12

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-3-methyl-butyl)-N-methyl-leucine (IIb) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 550 (M+1 for C₃₃ H₅₀ N₄ O₃); sticky solid; TLC: R_(f) 0.54 (10%MeOH/CH₂ Cl₂).

Example 13[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The preparation of(S)-2-(4-tert-butylbenzyl-methyl-amino)-4-methyl-pentanoic acid (IIc)##STR30## Step i: (S)-4-Methyl-2-methylamino-pentanoic acid (15 g, 103mmol) was dissolved in dioxane (100 mL), cooled to 0° C., then treatedwith H₂ SO₄ (10 mL) and isobutylene (100 mL). The mixture was stirredand allowed to come to room temperature over 1 hour. The reaction wasvented and poured into a rapidly stirred mixture of KOH (20.7 g) inwater, ice, and ether. The solution was filtered, and more ether wasadded. The organic layer was dried over Na₂ SO₄ and concentrated to give19.41 g (94%) of (S)4-methyl-2-methylamino-pentanoic acid tert-butylester.

MS: 202 (M+1 for C₁₁ H₂₃ N₁ O₂); TLC SiO₂, R_(f) 0.52 (10% MeOH/CH₂Cl₂).

Step ii: (S)-4-Methyl-2-methylamino-pentanoic acid tert-butyl ester (6g, 29.8 mmol) was dissolved in THF (250 mL) and treated withdiisopropylethylamine (7.8 mL, 44.7 mmol) and p-t-butyl-benzyl bromide(6.03 mL, 32.8 mL). The reaction was heated to 40° C. overnight, thenfiltered and concentrated. The residue was chromatographed on silica geleluting with 5% EtOAc/hexanes to give 5.1 g (50%) of(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acidtert-butyl ester.

MS: 349 (M+1 for C₃₂ H₃₇ N₁ O₂); TLC SiO₂, R_(f) 0.79 (25%EtOAc/hexanes).

Step, iii: (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid tert-butyl ester (0.5 g, 1.4 mmol) was dissolved in CH₂ Cl₂ (10 mL)and treated with TFA (1mL). After 1 hour, 0.5 mL TFA was added, followedby another 1 mL TFA at 2.5 hours. The reaction was stirred overnight,then concentrated to give(S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid(IIc).

MS: 292 (M+1 for C₁₈ H₂₇ N₁ O₂); mp: 110-112° C.; TLC SiO₂, R_(f) 0.5(12% MeOH/CH₂ Cl₂).

Step 2: Example 11:[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine.

MS: 601 (M+1 for C₃₈ H₅₃ N₃ O₃); mp 98-99° C.; TLC: R_(f) 0.70 (10%MeOH/CH₂ Cl₂).

Example 14

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide ismade in accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib)was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 613 (M+1 for C₃₉ H₅₃ N₃ O₃); sticky solid; TLC: R_(f) 0.60 (10%MeOH/CH₂ Cl₂).

Example 15

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide (Ic) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 656 (M+1 for C₄₁ H₅₈ N₄ O₃); mp 95-96 ° C.; TLC: R_(f) 0.17 (10%MeOH/CH₂ Cl₂).

Example 16

[S-(R*,R*)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 704 (M+1 for C₄₅ H₅₈ N₄ O₃); sticky solid; TLC: R_(f) 0.57 (10%MeOH/CH₂ Cl₂).

Example 17

S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 718 (M+1 for C₄₆ H₆₀ N₄ O₃); mp 93-95 ° C.; TLC: R_(f) 0.43 (10%MeOH/CH₂ Cl₂).

Example 18

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-(4-tert-butylbenzyl)-N-methyl-leucine (IIc) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 615 (M+1 for C₃₈ H₅₄ N₄ O₃); sticky solid; TLC: R_(f) 0.58 (10%MeOHCH₂ Cl₂).

Example 19 [S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The Preparation(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic Acid (IId) ##STR31##Step i: N-Me-O-Benzyl-L-Leucine (3.6 g, 15.3 mmol) was dissolved in THF(77 mL) and treated with diisopropylethylamine (21 mL, 122 mmol) and3-bromo-cyclohexene (3.5 mL, 30.6 mmol). The reaction was heated to 50°C. for 2 days. The reaction was filtered, and the solution wasconcentrated. The residue was chromatographed on silica gel eluting with8% ethyl acetate/hexanes to give 2.75 g (57%) of(S)-2-(cyclohexenyl-methyl-amino)-4-methyl-pentanoic acid benzyl ester.

MS: 317 (M+1 for C₂₀ H₂₉ N₁ O₂); TLC: SiO₂, R_(f) 0.86 (10% MeOH/CH₂Cl₂).

Step ii: (S)-2-(Cyclohexenyl-methyl-amino)-4-methyl-pentanoic acidbenzyl ester (2.87 g, 9.10 mmol) was dissolved in THF (50 mL) and shakenwith 20% Pd/C (0.2 g) under an H₂ atmosphere for 4 hours. The catalystwas removed by filtration through a pad of Celite, and the solution wasconcentrated to give 1.44 g (70%/0) of IId as a white solid.

MS: 228 (M+1 for C₁₃ H₂₅ N₁ O₂); TLC: SiO₂, R_(f) 0.27 (10% MeOH/CH₂Cl₂).

Step 2: Example 19:[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 1, exceptN-cyclohexyl-N-methyl-leucine (IId) was used instead ofN,N-dimethyl-L-leucine.

MS: 537 (M+1 for C₃₃ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 0.57 (10%MeOH/CH₂ Cl₂).

Example 20

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide is madein accordance with the process of Example 1, exceptN-cyclohexyl-N-methyl-leucine (IId) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib)was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 549 (M+1 for C₃₄ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 0.52 (10%MeOH/CH₂ Cl₂).

Example 21

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide is made in accordance with the processof Example 1, except N-cyclohexyl-N-methyl-leucine (IId) was usedinstead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide(Ic) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 592 (M+1 for C₃₆ H₅₄ N₄ O₃); sticky solid; TLC: R_(f) 0.29 (10%MeOH/CH₂ Cl₂).

Example 22

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-cyclohexyl-N-methyl-leucine (IId) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 640 (M+1 for C₄₀ H₅₄ N₄ O₃); sticky solid; TLC: R_(f) 0.53 (10%MeOH/CH₂ Cl₂).

Example 23

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, exceptN-cyclohexyl-N-methyl-leucine (IId) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 654 (M+1 for C₄₁ H₅₆ N₄ O₃); sticky solid; TLC: R_(f) 0.49 (10%MeOH/CH₂ Cl₂)

Example 24

[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, exceptN-cyclohexyl-N-methyl-leucine (IId) was used instead ofN,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If) was used instead of(S)2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 563 (M+1 for C₃₄ H₅₀ N₄ O₃); sticky solid; TLC: R_(f) 0.53 (10%MeOH/CH₂ Cl₂).

Example 25[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The preparation of(S)-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe): IIeis made in accordance with the process of IIb, exceptcyclohexanecarboxaldehyde was used instead of isovaleraldehyde.

Step 2: Example 25:[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine.

MS: 550 (M+1 for C₃₄ H₅₁ N₃ O₃); sticky solid; TLC: R_(f) 0.50 (10%MeOH/CH₂ Cl₂).

Example 26

[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid [²-(⁴ -benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide is made inaccordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(piperidin-1-yl)-propionamide (Ib)was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 562 (M+1 for C₃₅ H₅₁ N₃ O₃); sticky solid; TLC: R_(f) 0.46 (10%MeOH/CH₂ Cl₂).

Example 27

[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-ethyl)-propionamide(Ic) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 605 (M+1 for C₃₇ H₅₆ N₄ O₃); sticky solid; TLC: R_(f) 0.23 (10%MeOH/CH₂ Cl₂).

Example 28

[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one (Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 653 (M+1 for C₄₁ H₅₆ N₄ O₃); sticky solid; TLC: R_(f) 0.49 (10%MeOH/CH₂ Cl₂).

Example 29

[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-N-(1-benzyl-piperidin-4-yl)-propionamide(Ie) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 665 (M+1 for C₄₂ H₅₆ N₄ O₃); sticky solid; TLC: R_(f) 0.34 (10%MeOH/CH₂ Cl₂).

Example 30

[S-(R*,R*)]-2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 1, except(S)-2-(cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid (IIe) wasused instead of N,N-dimethyl-L-leucine, and(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one(If) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 553 (M+1 for C₃₃ H₅₂ N₄ O₃); sticky solid; TLC: R_(f) 0.54 (10%MeOH/CH₂ Cl₂).

General Procedure for the Preparation of Substituted Peptidylamines (IV)##STR32##

Example 31[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-but-2-enylamino)-pentanoylamino]-propionicacid tert-butyl ester ##STR33## Step 1: The Preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester

A solution of L-tyrosine-OBn (50.0 g, 0.184 mol) was dissolved indioxane (500 mL). The reaction vessel was charged with isobutylene (500mL) and concentrated sulfuric acid (50 mL). The reaction vessel wassealed and shaken for 64 hours. The reaction mixture was vented andpoured into a rapidly stirring mixture of KOH (104 g) in ice water 1000mL. The resulting mixture was extracted into ether (5×200 mL), and thecombined organic extracts were dried (MgSO₄), filtered, andconcentrated. The residue was purified by chromatography (silica gel,2:1 CHCl₃ /EtOAc). The residue obtained from the chromatographysolidified on standing to give the product as a tan solid (35.3 g, 59%).

Step 2: The Preparation of3-(4-Benzyloxy-phenyl)-2-{2-1(9H-fluoren-9-ylmethyl)-amino]-4-methyl-pentanoylamino}propionicacid tert-butyl ester

A solution of FMOC-leucine (10.3 g, 29 mmol) in 300 mL of DMP was cooledto 0° C. and treated with diisopropylethyl amine (73 mL) and HBTU (11.1g, 29.2 mmol). The resulting solution was stirred at 0° C. for 30minutes and treated with (S)-amino-3-(4-benzyloxy-phenyl) propionic acidtert-butyl ester (110 g, 36.9 mmol). The resulting solution was stirredfor 30 minutes at 0° C. and warmed to room temperature. The reactionmixture was poured into 500 mL of ether and washed sequentially with 1Naqueous HCl, saturated aqueous NaHCO₃ (100 mL), and brine (5×100 mL).The organic phase was collected, dried MgSO₄ and concentrated to neardryness. The residue was triturated with hexane. The product wascollected by suction filtration and air dried to give the title compoundas a white solid (12.16 g, 70%) mp 158-160° C.

Analysis Calculated for C₄₁ H₄₆ N₂ O₆ : C, 74.30; H, 7.00; N, 4.23.Found: C, 74.21; H, 7.25; N, 4.20.

Step 3: The Preparation of2-{2-Amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester

A solution of3-(4-benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methylpentanoylamino}-propionic acid tert-butyl ester (12.2 g, 20.0 mmol) in500 mL of tetrahydrofuran was treated with piperidine (80 mL). Theresulting solution was stirred at room temperature for 48 hours. Thereaction mixture was concentrated and the residue purified bychromatography (SiO₂, gradient elution EtOAc - 15% EtOH/EtOAc). Theresulting yellow solid was broken up in heptane to give the titlecompound as a white solid (6.77 g, 77%).

Step 4: Example 31: [S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-but-2-enylamino)-pentanoylamino]-propionicacid tert-butyl ester

A mixture of2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester (2 nmmol), diisopropyl ethylamine (3 mmol),1-bromo-3-methyl-2-butene (3 mmol) and anhydrous THF (30 mL) was stirredat 25° C. for 6 hours. The precipitate was filtered off. The reactionmixture was concentrated and purified by column chromatography on silicagel eluting with 25% EtOAc/hexanes to give the titled compound (600 mg,60% yield)

MS: 510 (M+1 for C₃₁ H₄₄ N₂ O₄); mp 70-71 ° C.; TLC: R_(f) 0.3 (25%EtOAc/hexanes).

Example 32

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[2-(4-tert-butyl-benzylamino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester is made in accordance with the process of Example31, except 4-tertbutylbenzylbromide was used instead of1-bromo-3-methyl-2-butene.

MS: 588 (M+1 for C₃₇ H₅₀ N₂ O₄); mp 89-90° C.; TLC: R_(f) 0.3 (20%EtOAc/hexanes).

Example 33

[S-(R*,R*)]-2-(2-Benzylamino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester is made in accordance with the process of Example47, except benzylbromide was used instead of 1 -bromo-3-methyl-2-butene.

MS: 532 (M+1 for C₃₃ H₄₂ N₂ O₄); mp 66-67° C.; TLC: R_(f) 0.7 (33%EtOAc/hexanes).

Example 34

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide ##STR34##Step 1: Example 35: [S-(R*,R*)]-4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step i: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide(7.0 g, 21.4 mmol) (Ia) was dissolved in CH₃ CN (75 mL) and treated withdiisopropylethylamine (3.72 mL, 21.4 mmol), N-Boc-N-Me-L-leucine (3.51g, 14.3 mmol), and HBTU (5.42 g, 14.3 mmol). The reaction was stirredfor 30 minutes and then concentrated. The residue was dissolved in EtOAc(300 mL), washed with saturated bicarbonate solution (2×300 mL) andbrine (300 mL), dried over Na₂ SO₄, and concentrated. The crude materialwas chromatographed on silica gel eluting with 25% EtOAc/hexanes to give7.0 g (88%) of{1-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester.

MS: 554 (M+1 for C₃₂ H₄₆ N₃ O₅); TLC: SiO₂, R_(f) 0.26 (8% MeOH/C₂ Cl₂).

Step ii: Example 35: [S-(R*,R*)]-4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

{1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester (4.0 g, 7.24 mmol) was dissolved in CH₂ Cl₂ (24mL) and treated with trifluoroacetic acid (16 mL). The reaction wasstirred for 15 minutes, then concentrated, diluted with EtOAc (300 mL),washed with bicarbonate solution (3×300 mL) and brine (300 mL), driedover Na₂ SO₄, and concentrated. The crude material was chromatographedon silica gel eluting with 8% MeOH/CH₂ Cl₂ to give 2.8 g (85%) ofExample 35. The hydrochloride salt of Example 34 was prepared bydissolving the free base in Et₂ O, adding 1 M HCl in Et₂ O, andconcentrating the solution in vacuo.

MS: 454 (M+1 for C₂₇ H₃₈ N₃ O₃); TLC: SiO₂, R_(f) 0.19 (8% MeOH/CH₂Cl₂).

Step 2: Example 34:[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

The HCl salt of Example 35 (0.5 g, 1.0 mmol) was dissolved in CH₂ Cl₂ (5mL) and treated with isovaleraldehyde (0.11 mL, 1.0 mmol). The reactionwas stirred for 30 minutes, then cooled to 0° C. and treated with sodiumtriacetoxyborohydride (0.32 g, 1.5 mmol). The reaction was allowed towarm to room temperature and stir overnight. The reaction was dilutedwith CH₂ Cl₂ (100 mL), washed with saturated bicarbonate solution (2×100mL) and brine (100 mL), dried over Na₂ SO₄, and concentrated. Theresidue was chromatographed on silica gel eluting with 8% acetone/CH₂Cl₂ to give 0.27 g (52%) of the title compound.

MS: 525 (M+1 for C₃₂ H₄₉ N₃ O₃); sticky solid; TLC: SiO₂, R_(f) 0.53(10% MeOH/CH₂ Cl₂).

Example 36

[S-(R*,R*)]-2-[(3,3-Dimethyl-butyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 34, except3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.

MS: 539 (M+1 for C₃₃ H₅₁ N₃ O₃); sticky solid; TLC: R_(f) 0.55 (50%hexanes/EtOAc).

Example 37

[S-(R*,R*/S*)]-2-Diethylamino-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 34, except acetaldehyde wasused instead of isovaleraldehyde and N-Boc-N-Methyl-(D,L)-Leucine wasused instead of N-Boc-N-methyl-L-leucine for the intermediatespreparation.

MS: 501 (M+1 for C₃₀ H₄₅ N₃ O₃); sticky solid; TLC: R_(f) 0.4 (50%hexanes/EtOAc).

Example 38

[S-(R*,R*)]-2-[(4-tert-Butyl-cyclohexyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 34, except4-tert-butyl-cyclohexanone was used instead of isovaleraldehyde.

MS: 473 (M+1 for C₂₇ H₅₇ N₃ O₃); sticky solid; TLC: R_(f) 0.7 (66%hexanes/EtOAc).

Example 39

[S-(R*,R*)]-4-Methyl-2-[methyl-(4-methyl-cyclohexyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 34, except4-methyl-cyclohexanone was used instead of isovaleraldehyde.

MS: 550 (M+1 for C₃₄ H₅₁ N₃ O₃); sticky solid; TLC: R_(f) 0.4 (66%hexanes/EtOAc).

Example 40

[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 34, except4-(dimethylamino)-benzaldehyde was used instead of isovaleraldehyde.

MS: 588 (M+1 for C₃₆ H₅₀ N₄ O₃); sticky solid; TLC: R_(f) 0.2 (66%hexanes/EtOAc).

Example 41

[S-(R*,R*)]-2-(Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 34, except n-butyraldehyde wasused instead of isovaleraldehyde.

MS: 511 (M+1 for C₃₁ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.5 (50%hexanes/EtOAc).

Example 42

[S-(R*,R*)]-2-(Isobutyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 34, except iso-butyraldehyde wasused instead of isovaleraldehyde.

MS: 515 (M+1 for C₃₁ H₄₇ N₃ O₃); mp 75-76° C.; TLC: R_(f) 0.8 (50%hexanes/EtOAc).

Example 43

[S-(R*,R*)]-4-Methyl-2-methylamino-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 35, except(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one (Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.

MS: 558 (M+1 for C₃₄ H₄₄ N₄ O₃); sticky solid; TLC: R_(f) 0.6 (10%MeOH/CH₂ Cl₂).

Example 44

[S-(R*,R*)]-3-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 34, exceptN-Boc-N-methyl-iso-leucine was used instead of exceptN-Boc-N-methyl-leucine.

MS: 524 (M+1 for C₃₂ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 0.63 (10%MeOH/CH₂ Cl₂).

Example 45

[S-(R*,R*)]-4Methyl-2-[ethyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 34, except N-Boc-N-ethyl-leucinewas used instead of N-Boc-N-methyl-leucine.

MS: 538 (M+1 for C₃₃ H₅₁ N₃ O₃); sticky solid; TLC: R_(f) 0.71 (10%MeOH/CH₂ Cl₂).

Example 46

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-butyric acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 34, except N-Boc-N-methyl-valinewas used instead of N-Boc-N-methyl-leucine.

MS: 510 (M+1 for C₃₁ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.59 (10%MeOH/CH₂ Cl₂).

Example 47[S-(R*,R*)]-2-(Cyclohex-2-enyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Example 35)(1.0 mmol) was dissolved in THF (10 mL) and treated with3-bromocyclohexene (1.5 mmol) and diisopropylethylamine (3 mmol). Thereaction was stirred at 50° C. for 18 hours. Then the reaction mixturewas allowed to cool to room temperature and concentrated to dryness. Theresidue was chromatographed on silica gel eluting with a gradient of10-30% acetone/CH₂ Cl₂ to give the title compound with the yields of50%.

MS: 535 (M+1 for C₃₃ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.5 (50%hexanes/EtOAc).

Example 48[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

2-(Methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.5 mmol)was dissolved in THF (10 mL) and treated with 4-tert-butyl-benzylbromide (0.75 mmol) and diisopropylethylamine (1.5 mmol). The reactionwas stirred at 50° C. for 15 hours. Then the reaction mixture wasallowed to cool to room temperature and concentrated to dryness. Theresidue was chromatographed on silica gel eluting with a gradient of 25%EtOAc/Hexanes to give the title compound with the yield of 40%.

MS: 601 (M+1 for C₃₈ H₅₃ N₃ O₃); mp 98-99° C.; TLC: R_(f) 0.70 (10%MeOH/CH₂ Cl₂).

Example 49 [S-(R*,R*)]-2-(Cyclohex-2-enylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The preparation of 4-Methyl-2-amino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Va) is madein accordance with the process of Example 35, except N-Boc-leucine wasused instead of N-Boc-N-methyl-leucine.

Step 2: Example 49:[S-(R*,R*)]-2-(Cyclohex-2-enylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 47, except4-methyl-2-amino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Va) was used instead of4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.

MS: 521 (M+1 for C₃₂ H₄₅ N₃ O₃); sticky solid; TLC: R_(f) 0.7 (50%hexanes/EtOAc).

Example 50

[S-(R*,R*)]-2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 47 except4-methyl-2-amino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Va) was usedinstead of 4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide, and4-tertbutylbenzylbromide was used instead of 3-bromocyclohexene.

MS: 586 (M+1 for C₃₇ H₅₁ N₃ O₃); TLC: R_(f) 0.8 (50% hexanes/EtOAc).

Example 51

[S-(R*,R*)]4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is madein accordance with the process of Example 47 except4-bromo-2-methyl-2-butene was used instead of 3-bromocyclohexene.

MS: 523 (M+1 for C₃₂ H₄₇ N₃ O₃); mp 91-92° C.; TLC: R_(f) 0.4 (EtOAc).

Example 52 [S-(R*,R*)]-2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide

Step 1: The preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) (described in Example 4)

Step 2: The preparation of [S-(R*,R*)]-2-Amino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1 -yl)-2-oxo-ethyl]-amide(Vb) is made in accordance with the process of Example 35, except(S)-2-amino-3-(4-benzyloxy-phenyl)-1-(4-benzyl-piperazin-1-yl)-propan-1-one(Id) was used instead of(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide, andN-Boc-leucine was used instead of N-Boc-N-methyl-leucine.

Step 3: Example 52:[S-(R*,R*)]-2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 47, except2-amino-4-methyl-pentanoic acid [1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide(Vb)was used instead of 4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide, and4-tert-butylbenzyl-bromide was used instead of 3-bromocyclohexene. MS:699 (M+1 for C₄₄ H₅₆ N₄ O₃); mp 56-57° C.; TLC: R_(f) 0.7 (EtOAc).

Example 53

[S-(R*,R*)]-4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amideis made in accordance with the process of Example 47, except2-amino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin- 1 -yl)-2-oxo-ethyl]-amide(Vb) was used instead of 4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide, and4-bromo-2-methyl-2-butene was used instead of 3-bromocyclohexene.

MS: 616 (M+1 for C₃₈ H₅₀ N₄ O₃); sticky solid; TLC: R_(f) 0.4 (EtOAc).

Example 54

[S-(R*,R*)]-2-(Benzyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the process of Example 47 except benzylbromide was usedinstead of 3-bromocyclohexene.

MS: 557 (M+1 for C₃₄ H₄₅ N₃ O₃); mp 134-135° C.; TLC: R_(f) 0.7 (33%hexanes/EtOAc).

Example 55[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide##STR35## Step 1: The Preparation of(S)-[1-tert-Butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-carbamic acidtert-butyl ester (VIa)

(S)-[1-tert-Butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-carbamic acid (16.0g, 51.6 mmol) was dissolved in DMF (258 mL) and treated withdiisopropylethylamine (13.5 mL, 77.3 mmol), tert-butylamine (5.4 mL,51.6 mmol), and HBTU (19.57 g, 51.6 mmol). The reaction was stirred for4 hours, then diluted with CH₂ Cl₂ (500 mL), washed with saturatedbicarbonate solution (2×500 mL) and brine (500 mL), dried over Na₂ SO₄,and concentrated to give 18.3 g (97%) of VIa as a pale orange solid.

MS: 366 (M+1 for C₁₈ H₂₇ N₃ O₅); TLC SiO₂, R_(f) 0.62 (50%EtOAc/hexanes).

Step 2: The Preparation of(S)-2-Amino-N-tert-butyl-3-(4-nitro-phenyl)-propionamide (VIb)

(S)-[1-tert-Butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-carbamic acidtert-butyl ester (9.0 g, 24.6 mmol, VIa) was dissolved in CH₂ Cl₂ (60mnL) and treated with TFA (50 mL). The solution was stirred for 25minutes, then concentrated in vacuo and pumped on briefly under highvacuum. The residue was dissolved in EtOAc (300 mL), washed withsaturated bicarbonate solution (2×300 mL) and brine (300 mL), dried overNa₂ SO₄, and concentrated. The crude product was chromatographed onsilica gel eluting with 8% MeOH/CH₂ Cl₂ to give 2.41 g (37%) of VIb.

MS: 266 (M+1 for C₁₃ H₁₉ N₃ O₃); TLC SiO₂, R_(f) 0.48 (8% MeOH/CH₂ Cl₂).

Step 3: The Preparation of[S-(R*,R*)]-{1-[1-tert-Butylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester (VIc)

(S)-2-Amino-N-tert-butyl-3-(4-nitro-phenyl)-propionamide (2.41 g, 9.08mmol, VIb) was dissolved in DMF (45 mL), and treated withdiisopropylethylamine (3.15 mL, 18.16 mmol), N-Boc-N-Me-leucine (2.23 g,9.08 mmol), and HBTU (3.44 g, 9.08 mmol). The reaction was stirred for1.25 hours, then diluted with EtOAc (300 mL), washed with saturatedbicarbonate solution (2×300 mL) and brine (300 mL), dried over Na₂ SO₄,and concentrated to give 4.44 g (99%) of VIc.

MS: 494 (M+1 for C₂₅ H₄₀ N₄ O₆); TLC SiO2, R_(f) 0.8 (10% MeOH/CH₂ Cl₂).

Step 4: The Preparation of [S-(R*,R*)]-4-Methyl-2-methylamino-pentanoicacid [1-tert-butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-amide (VId)

{1-[1-tert-Butylcarbamoyl-2-(4-nitro-phenyl)-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester (4.43 g, 8.99 mmol,VIc) was dissolved in CH₂ Cl₂(30 mL) and treated with TFA (21 mL). The solution was stirred for 25minutes, then concentrated in vacuo and pumped on briefly under highvacuum. The residue was diluted with EtOAc (300 mL), washed withsaturated bicarbonate solution (3×300 mL) and brine (300 mL), dried overNa₂ SO₄, and concentrated to give 3.51 g (99%) of VId.

MS: 394 (M+1 for C₂₀ H₃₂ N₄ O₄); mp 162-164° C.

Step 5: [S-(R*,R*)]-2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[1-tert-butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-amide (VIe)

4-Methyl-2-methylamino-pentanoic acid[1-tert-butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-amide (3.41 g, 8.69mmol, VId) was dissolved in THF (170 mL), and treated withdiisopropylamine (6.1 mL, 34.8 mmol), and 4-tert-butyl-benzyl bromide(1.76 mL, 9.56 mmol). The reaction was heated to 40° C. overnight, thenthe volume was reduced by one-half under reduced pressure and heated to40° C. for 2 hours. The reaction was filtered, and the solution wasconcentrated in vacuo. The reside was purified by flash chromatographyon silica gel eluting with 33% ethyl acetate/hexanes to give 3.95 g(84%) of VIe. MS: 540 (M+1 for C₃₁ H₄₆ N₄ O₄); TLC SiO₂, R_(f) 0.1 (33%EtOAc/hexanes).

Step 6:[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-amino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (VIf)

[S-(R*,R*)]-2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[1-tert-butylcarbamoyl-2-(4-nitro-phenyl)-ethyl]-amide (0.96 g, 1.78mmol, VIe) was dissolved in MeOH (50 mL) and shaken under an H₂atmosphere with Raney Nickel (0.2 g). The catalyst was filtered and thesolution concentrated in vacuo to give 0.89 g (98%) of VIf as a whitefoam.

MS: 510 (M+1 for C₃₁ H₄₈ N₄ O₂); mp 80-81° C.; TLC R_(f) 0.36 (33%EtOAc/hexanes).

Step 7: Example 55:[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-amino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.89 g,1.75 mmol) was dissolved in toluene (18 mL) and treated withdiisopropylamine (0.61 mL, 3.5 mmol), and benzyl bromide (0.21 mL, 1.75mmol). The reaction was stirred at room temperature overnight. After 24hours, diisopropylamine (0.35 mL, 0.2 eq.) and benzyl bromide (0.021 mL,0.2 eq.) were added, and the reaction was stirred for 5 hours. Thereaction was concentrated and chromatographed on silica gel to giveExample 55.

MS: 600 (M+1 for C₃₈ H₅₄ N₄ O₂); mp 74-75° C.; TLC SiO₂, R_(f) 0.66 (33%EtOAc/hexanes).

Example 56 [S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

O-Benzyl-L-tyrosine-t-butyl-amide (Ia, 0.5 g, 1.53 mmol) was dissolvedin DMF (8 mL) and treated with diisopropylethylamine (0.8 mL, 4.6 mmol),N-cyclohexyl-N-methyl-leucine (Iid, 0.34 g, 1.53 mmol), and HBTU (0.58g, 1.53 mmol). The reaction was stirred for 2 hours, then diluted withEtOAc (100 mL), washed with saturated bicarbonate solution (2×100 mL),brine (100 mL), dried over Na₂ SO₄, and concentrated. The residue waschromatographed on silica gel eluting with 50% EtOAC/hexane. Theresulting material was chromatographed again on silica gel eluting with8% acetone/CH₂ Cl₂ to give 0.11 g (14%) of the title compound. MS: 537(M+1 for C₃₃ H₄₉ N₃ O₃); TLC: SiO₂, R_(f) 0.57 (10% MeOH/CH₂ Cl₂).

Examples 57-105

Multiple Parallel Synthesis Using Kaiser Oxime Resin and Solid PhaseQuenching Agent

Step 1: Synthesis of highly loaded Boc-Tyr(Bn)-OH resin (Ia)

In a 100-mL reaction vessel equipped with fritted glass filter, 10 gKaiser oxime resin (0.91 mmol/g load) was washed sequentially with CH₂Cl₂ (3×) and DMF (3×). In a separate flask, a solution of 8.44 gBoc-Tyr(Bn)-OH (22.74 mmol) in 40 mL DMF was treated with 7.82 mLdiisopropylethylamine (45.5 mmol), 8.62 g HBTU (22.74 mmol) and 3.48 gHOBt (22.74 mmol). The resulting solution was stirred for 10 minutes andwas added to the reaction vessel containing the washed Kaiser oximeresin. The suspension was shaken overnight at room temperature, thenwashed five times with DMF. The entire procedure was repeated threetimes After the third coupling, the suspension was washed with DMF (3×)and DCM (3×) to give Ia.

Step 2: The Preparation of H-Tyr(OBn)-OH coupled to Kaiser oxime resin(Ib)

The resin (Ia, 10 g, loading between 0.6-0.8 mmol/g) was washed withdimethylformamide (3×) and CH₂ Cl₂ (3×), and then treated with asolution of 25% trifluoroacetic acid in CH₂ Cl₂ (v/v) for 30 minutes.The resin was then washed with CH₂ Cl₂ (3×), 5% diisopropylamine in CH₂Cl₂ (v/v), CH₂ Cl₂ (3×), and dimethylformamide (3×).

Step 3: The Preparation of N,N-Leucine-tyrosine(OBn)-Kaiser oxime resin(Ic)

A solution of N,N-disubstituted leucine (12 mmol) in 50% DMF/NMP (40 mL)was treated with diisopropylethylamine (4.18 mL), HBTU (12 mmol), and Ib(prepared from Step 2), and the resulting suspension was shaken for 1hour. The resin (Ic) was washed with DMF (5×) and collected.

Step 4: The Preparation of the Polymer-supported Isocyanate (Id)

A suspension of aminomethyl resin (Fluka, 1.1 mmol N/g resin, 15 g, 16.5mmol) in DCM (150 mL) was treated with Et₃ N (11.5 mL, 83 mmol) andtriphosgene (3.25 g, 2 mmol equivalents of phosgene) and shaken 5 hoursat room temperature. The resulting isocyanate resin was filtered andwashed DCM (2×200 mL), CHCl₃ (2×200 mL), Et₂ O (1×200 mL), THF (1×200mL), Et₂ O (1×200 mL), THF (1×200 mL), Et₂ O (1×200 mL). The resin wasthen dried at 35° C. to 40° C., 25 mmHg for 24 hours. Yield (15 g), IR(KBr) 2260 (N═C═O).

Step 5: Synthesis of the Substituted Peptidylamines

The resin (Ic) prepared from Step 3 was suspended in CH2Cl₂, and 1.5equivalents of the appropriate amine was added. The suspension wasshaken for 48 hours. After the reaction was completed, additional CH₂Cl₂ was added, with 1 equivalent of Polymer-supported Isocyanate (Id).After the suspension was shaken for 24 hours, the resin was filteredoff, and the solvent was evaporated yielding the amorphous product. Thepurity of the product was analyzed by HPLC: A Model 1050 (HewlettPackard, Palo Alto, Calif.) system was used for the analytical HPLC.Solvent A: 0.1% TFA/water and solvent B: 0.09% TFA/acetonitrile, with alinear gradient of 2% B/min starting at 0%. Vydac (The SeparationsGroup, Hesperia, Calif.) C18, 300 Å pore size, 5 μM particle size,4.6×250 mm column was used, with a flow rate of I mL/min.

Example 57[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide

Step 1: Method A of the synthesis of(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (IIb)##STR36## Step i: N-Methyl-O-benizyl-L-leucine p-tosylate salt (4.01 g,9.84 mmol) was dissolved in CH₂ Cl₂ (50 mL) and treated withisovaleraldehyde (1.06 mL, 9.84 mmol). The reaction was stirred at roomtemperature for 30 minutes and then cooled to 0° C. Sodiumtriacetoxyborohydride (3.13 g, 14.8 mmol) was added, and the reactionwas allowed to warm to room temperature and stir overnight. The reactionwas diluted with CH₂ Cl₂ (400 mL). The organic layer was washed twicewith saturated bicarbonate solution (2×400 mL), once with brine (400mL), and then dried over Na₂ SO₄. The solution was filtered,concentrated, and the crude material chromatographed on silica geleluting with 10% EtOAc/hexanes to give 2.86 g (90%) of(S)-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid benzylester as a pale oil.

MS: 306 (M+1 for C₁₉ H₃₁ N₁ O₂); TLC: SiO₂, R_(f) 0.33(10%EtOAc/hexanes).

Step ii: (S)-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid.The benzyl ester (0.89 g, 2.89 mmol) was dissolved in THF (75 mL) andshaken with 20% Pd/C (0.1 g) under an H₂ atmosphere (52 psi) for 30minutes. The catalyst was removed by filtration through a pad of Celite,and the solution was concentrated to give 0.50 g (81%) of IIb as a whitesolid.

MS: 216 (M+1 for C₁₂ H₂₅ N₁ O₂); TLC: SiO₂, R_(f) 0.32 (10% MeOH/CH₂Cl₂).

Step 1: Method B of the synthesis of(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (IIb)

Step i: A vessel containing 100 g of L-Leucine, 1600 mL of ethanol, 8 gof 2% Pd/C, and 131.5 g of isovaleraldehyde was shaken under hydrogen.After the reaction was finished, the ethanol solution was collected byfiltration. Then 300 mL of concentrated HCl was added to thePd/C-compound mixture, and the mixture was filtered again to give thesecond filtrate. The second filtration provided the product inconcentrated HCl, and it was added NaOH to pH 6.5. The productprecipitated out as a white solid, and it was collected by filtration.The crude product was washed with water (200 mL) and acetone (300 mL),then it was dried under vacuum to yield N-(2-methylbutyl)-leucine (50g); mp 275° C. (dec.).

MS: 202 (M+1 for C₁₁ H₂₃ N₁ O₂).

Analysis calculated for C₁₁ H₂₃ N₁ O₂ : C, 65.63; H, 11.52; N, 6.96.Found: C, 65.50; H, 11.40; N, 6.88.

Step ii: A vessel containing 48 g of N-(2-methylbutyl)-L-leucine, 1.5 Lof ethanol, 50 mL of CH₂ O (37%, 3 eq.), and 3.0 g of 20% Pd/C wasshaken under hydrogen. After the reaction was finished, the ethanolsolution was collected by filtration. The ethanol solution wasconcentrated to dryness. Water (30 mL) was added to help removing CH₂ O,then it was concentrated to dryness; this step was repeated three times.The crude product was stirred with hot acetone (200 mL) for 2 hours andcontinued stirring at 25° C. for another 18 hours. Then the product wascollected by filtration and dried under vacuum to yield(S)4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (IIb) (40g); mp 159-160° C. (dec.). MS: 216 (M+1 for C₁₂ H₂₅ N₁ O₂).

Analysis calculated for C₁₂ H₂₅ N₁ O₂ : C, 66.93; H, 11.70; N, 6.50.Found: C, 66.72; H, 11.99; N, 6.45.

Step 2: The Preparation ofN-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn)-Kaiser oxime resin(IIc)

A solution of Ilb (4.55 mmol) in 30 mL of DMF was treated withdiisopropylethylamine (9.1 mmol), HBTU (4.55 mmol), Ib, and HOBt (4.55mmol), and the resulting suspension was shaken for 1 hour. The resin waswashed with DMF (5×) and collected to yield Ilc.

Step 3: The Preparation of[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide

The resin (IIc) was suspended in CH₂ Cl₂ and 1.5 equivalents of2-morpholin-4-yl-ethylamine. The suspension was shaken for 48 hours.After the reaction was completed, additional amount of CH₂ Cl₂ and 1equivalent of Polymer-supported Isocyanate were added. After thesuspension was shaken for 24 hours, the resin was filtered off, and thesolvent was evaporated to yield the title product.

MS: 581 (M+1); HPLC retention Time: 22.44 minutes.

Example 58

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except 2-(2-aminoethyl)pyridine was used instead of2-morpholin-4-yl-ethylamine.

MS: 573.5 (M+1); HPLC retention Time: 22.69 minutes.

Example 59

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except histamine was used instead of 2-morpholin-4-yl-ethylamine.

MS: 576.5 (M+1); HPLC retention Time: 22.57 minutes.

Example 60

[S(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except N¹ -benzyl-ethane-1,2-diamine was used instead of2-morpholin-4-yl-ethylamine.

MS: 601.3 (M+1); HPLC retention Time: 24.98 minutes.

Example 61

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide wasprepared in accordance with the procedure of Example 57 (Step 3), exceptthiomorpholine was used instead of 2-morpholin-4-yl-ethylamine.

MS: 554.5 (M+1); HPLC retention Time: 29.60 minutes.

Example 62

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except 2-amino-2-methyl-propane-1,3-diol was used instead of2-morpholin-4-yl-ethylamine.

MS: 570.5 (M+1); HPLC retention Time: 25.62 minutes.

Example 63

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except 1 -methoxymethyl-propylamine was used instead of2-morpholin-4-yl-ethylamine.

MS: 554.5 (M+1); HPLC retention Time: 28.5,28.7 minutes.

Example 64

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide was prepared inaccordance with the procedure of Example 57 (Step 3), except2-pyrrolidin-1-yl-ethylamine was used instead of2-morpholin-4-yl-ethylamine.

MS: 565.5 (M+1); HPLC retention Time: 22.8 minutes.

Example 65

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except piperidin-4-ol was used instead of 2-morpholin-4-yl-ethylamine.

MS: 552.5 (M+1); HPLC retention Time: 25.1 minutes.

Example 66

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except 2-(2-amino-ethylamino)-ethanol was used instead of2-morpholin-4-yl-ethylamine.

MS: 555.5 (M+1); HPLC retention Time: 22.3 minutes.

Example 67

[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except 1-benzyl-pyrrolidin-3-ylamine was used instead of2-morpholin-4-yl-ethylamine.

MS: 627.6 (M+1); HPLC retention Time: 25.3 minutes.

Example 68

[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 57 (Step 3),except N¹ -benzyl-ethane-1,2-diamine was used instead of2-morpholin-4-yl-ethylamine, and[S-(R*,R*)]-4-methyl-2-morphlin-4-yl-pentanoic acid-tyrosine(OBn)-Kaiseroxime resin was used instead of IIc. (Step 3)

[S-(R*,R*)]-4-methyl-2-morphlin-4-yl-pentanoic acid-tyrosine(OBn)-Kaiseroxime resin was prepared in accordance with the procedure of Example 57(Step 2), except (S)-4-methyl-2-morpholin-4-yl-pentanoic acid was usedinstead of (S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid(IIb).

(S)-4-methyl-2-morpholin-4-yl-pentanoic acid was made in accordance withthe literature procedure (Kwapiszewki W. and Bialasiewicz W., Acta Pol.Pharm., 1994;51(3):227-229).

MS: 587.3 (M+1); HPLC retention Time: 30.72 minutes.

Example 69

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 1-benzyl-pyrrolidin-3-ylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

MS: 613.3 (M+1); HPLC retention Time: 21.80 minutes.

Example 70

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide was preparedin accordance with the procedure of Example 68 (Step 3), exceptpiperidine was used instead of N¹ -benzyl-ethane- 1,2-diamine.

MS: 522.3 (M+1); HPLC retention Time: 26.21 minutes.

Example 71

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amidewas prepared was prepared in accordance with the procedure of Example 57(Step 3), except N¹ -benzyl-ethane-1,2-diamine was used instead of2-morpholin4-yl-ethylamine andN-methyl-N-(tetrahydro-pyran-4-yl)-leucine-tyrosine(OBn)-Kaiser oximeresin was used instead of IIc. (Step 3)

N-methyl-N-(tetrahydro-pyran4-yl)-leucine-tyrosine(OBn)-Kaiser oximeresin was prepared in accordance with the procedure of Example 57 (Step2), except 4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid wasused instead of (S)-4-methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoicacid (IIb).

4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid was made inaccordance with the procedure of Example 57 (Step 1), excepttetrahydro-4H-pyran-4-one was used instead of isovaleraldehyde.

MS: 615.3 (M+I); HPLC retention Time: 21.96 minutes.

Example 72

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide wasprepared in accordance with the procedure of Example 71 (Step 3), exceptthiomorpholine was used instead of N¹ -benzyl-ethane- 1,2-diamine.

MS: 568.3 (M+1); HPLC retention Time: 26. 1 minutes.

Example 73

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylearbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 2-amino-2-methyl-propan-1-ol was used instead of N¹-benzyl-ethane-1,2-diamine.

MS: 554.3 (M+1); HPLC retention Time: 23.0 minutes.

Example 74

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 2-amino-2-methyl-propane-1,3-diol was used instead of N¹-benzyl-ethane-1,2-diamine.

MS: 584.3 (M+1); HPLC retention Time: 21.8 minutes.

Example 75

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 1 -methoxymethyl-propylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

MS: 568.4 (M+1); HPLC retention Time: 25.1, 25.5 minutes.

Example 76

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 1-benzyl-pyrrolidin-3-ylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

MS: 641.4 (M+1); HPLC retention Time: 22.1 minutes.

Example 77

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 2-piperidin-1-yl-ethylamine was used instead of N¹-benzyl-ethane- 1,2-diamine.

MS: 593.4 (M+1); HPLC retention Time: 20.1 minutes.

Example 78

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was preparedin accordance with the procedure of Example 71 (Step 3), exceptt-butylamine was used instead of N¹ -benzyl-ethane-1,2-diamine.

MS: 538.3 (M+1); HPLC retention Time: 27.2 minutes.

Example 79

[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide was preparedin accordance with the procedure of Example 71 (Step 3), exceptpiperidine was used instead of N¹ -benzyl-ethane-1,2-diamine.

MS: 550.4 (M+1); HPLC retention Time: 26.5 minutes.

Example 80

[S-(R*,R*)]-2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: The Preparation of(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Ia) wasprepared as Example 1 (Step 1).

Step 2: The Preparation of [S-(R*,R*)]-4-Methyl-2-methylamino-pentanoicacid [2-(4benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step i: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide(7.0 g, 21.4 mmol) (Ia) was dissolved in CH₃ CN (75 mL) and treated withdiisopropylethylamine (3.72 mL, 21.4 mmol), N-Boc-N-Me-L-leucine (3.51g, 14.3 mmol), and HBTU (5.42 g, 14.3 mmol). The reaction was stirredfor 30 minutes and then concentrated. The residue was dissolved in EtOAc(300 mL), washed with saturated bicarbonate solution (2×300 mL) andbrine (300 mL), dried over Na₂ SO₄, and concentrated. The crude materialwas chromatographed on silica gel eluting with 25% EtOAc/hexanes to give7.0 g (88%) of[S-(R*,R*)]-{1-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester.

MS: 554 (M+1 for C₃₂ H₄₆ N₃ O₅); TLC: SiO₂, R_(f) 0.26 (8% MeOH/CH₂Cl₂).

Step ii:[S-(R*,R*)]-{1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamicacid tert-butyl ester (4.0 g, 7.24 mmol) was dissolved in CH₂ Cl₂ (24mL) and treated with trifluoroacetic acid (16 mL). The reaction wasstirred for 15 minutes, then concentrated, diluted with EtOAc (300 mL),washed with bicarbonate solution (3×300 mL) and brine (300 mL), driedover Na₂ SO₄, and concentrated. The crude material was chromatographedon silica gel eluting with 8% MeOH/CH₂ Cl₂ to give 2.8 g (85%) of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.

MS: 454 (M+1 for C₂₇ H₃₈ N₃ O₃); TLC: SiO₂, R_(f) 0.19 (8% MeOH/CH₂Cl₂).

Step 3: Example 80:[S-(R*,R*)]-2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

[S-(R*,R*)]-4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.3 g, 0.66mmol) was dissolved in CH₂ Cl₂ (5 mL) and treated with4-fluorobenzaldehyde (0.082 g, 0.66 mmol). The reaction was stirred for30 minutes, then cooled to 0° C. and treated with sodiumtriacetoxyborohydride (0.21 g, 1 mmol). The reaction was allowed to warmto room temperature and stirred overnight. The reaction was diluted withEtOAc (100 mL), washed with saturated bicarbonate solution (2×100 mL)and brine (100 mL), dried over Na₂ SO₄, and concentrated. The residuewas chromatographed on silica gel eluting with 6% MeOH/CH₂ Cl₂ to give0.29 g (78%) of the title compound.

MS: 562 (M+1 for C₃₄ H₄₄ N₃ O₃ F₁); mp 125-126° C.; TLC: R_(f) 0.56 (6%MeOH/CH₂ Cl₂).

Example 81

[S-(R*,R*)]-2-[(4-Bromo-benzyl)-methyl-amino]4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that4-bromobenzaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 623 (M+1 for C₃₄ H₄₄ N₃ O₃ Br₁); mp 122-123° C.; TLC: Rf 0.47 (6%MeOH/CH₂ Cl₂).

Example 82

[S-(R*,R*)]-2-[(4-Hydroxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that4-hydroxybenzaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 560 (M+1 for C₃₄ H₄₅ N₃ O₄); mp 123-124° C.; TLC: R_(f) 0.39 (6%MeOH/CH₂ Cl₂).

Example 83

[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin4-ylmethyl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that4-pyridinecarboxaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 545 (M+1 for C₃₃ H₄₄ N₄ O₃); mp: 135-136° C.; TLC: R_(f) 0.17 (5%MeOH/CH₂ Cl₂).

Example 84

[S-(R*,S*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80, except thatN-Boc-N-Me-D-leucine was used instead of N-Boc-N-Me-L-leucine in Step 2(i), and isovaleraldehyde was used instead of 4-fluorobenzaldehyde inStep 3.

MS: 524 (M+1 for C₃₂ H₄₉ N₃ O₃); sticky solid; TLC: R_(f) 067 (10%MeOH/CH₂ Cl₂).

Example 85[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoylamino]-propionicacid tert-butyl ester

Step 1: The Preparation of (S)-2-Amino-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester

A solution of L-tyrosine-OBn (50.0 g, 0.184 mol) was dissolved indioxane (500 mL). The reaction vessel was charged with isobutylene (500mL) and concentrated sulfuric acid (50 mL). The reaction vessel wassealed and shaken for 64 hours. The reaction mixture was vented andpoured into a rapidly stirring mixture of KOH (104 g) in ice water (1000mL). The resulting mixture was extracted into ether (5×200 mL), and thecombined organic extracts were dried (MgSO₄), filtered and concentrated.The residue was purified by chromatography (silica gel, 2:1 CHCl₃/EtOAc). The residue obtained from the chromatography solidified onstanding to give the product as a tan solid (35.3 g, 59%).

Step 2: The Preparation of[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methyl-pentanoylamino}-propionicacid tert-butyl ester

A solution of FMOC-leucine (10.3 g, 29 mmol) in 300 mL of DMF was cooledto 0° C. and treated with diisopropylethyl amine (73 mL) and HBTU (11.1g, 29.2 mmol). The resulting solution was stirred at 0° C. for 30minutes and treated with (S)-2-amino-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester (110 g, 36.9 mmol). The resulting solution wasstirred for 30 minutes at 0° C. and warmed to room temperature. Thereaction mixture was poured into 500 mL of ether and washed sequentiallywith IN aqueous HCl, saturated aqueous NaHCO₃ (100 mL) and brine (5×100mL). The organic phase was collected, dried over MgSO₄ and concentratedto near dryness. The residue was triturated with hexane. The product wascollected by suction filtration and air dried to give the title compoundas a white solid (12.16 g, 70%); mp 158-160° C.

Analysis calculated C₄₁ H₄₆ N₂ O₆ :

C, 74.30; H, 7.00; N, 4.23.

Found: C, 74.21; H, 7.25; N, 4.20.

Step 3: The Preparation of[S-(R*,R*)]-2-{2-Amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester

A solution of[S-(R*,R*)]-3-(4-benzyloxy-phenyl)-2-{2-[(9H-fluoren-9-ylmethyl)-amino]-4-methylpentanoylamino}-propionic acid tert-butyl ester (12.2 g, 20.0 mmol) in500 mL of tetrahydrofuran was treated with piperidine (80 mL). Theresulting solution was stirred at room temperature for 48 hours. Thereaction mixture was concentrated and the residue purified bychromatography (SiO2, gradient elution EtOAc - 15% EtOH/EtOAc). Theresulting yellow solid was broken up in heptane to give the titlecompound as a white solid (6.77 g, 77%).

Step 4: Example 85:[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoylamino]-propionicacid tert-butyl ester was made in accordance with the procedure ofExample 80 (Step 3), except that[S-(R*,R*)]-2-{2-amino4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester was used instead of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide, andtetrahydropyran-4-one was used instead of 4-fluorobenzaldehyde.

MS: 525 (M+1 for C₃₁ H₄₅ N₃ O₄); sticky solid; TLC: R_(f) 0.56 (7%MeOH/CH₂ Cl₂).

Example 86

[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except thatacetone was used instead of 4-fluorobenzaldehyde.

MS: 497 (M+1 for C₃₀ H₄₅ N₃ O₃); TLC: R_(f) 0.32 (20% acetone/CH₂ Cl₂).

Example 87

[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide as madein accordance with the procedure of Example 80 (Step 3), except thattetrahydropyran-4-one was used instead of 4-fluorobenzaldehyde.

MS: 539 (M+1 for C₃₂ H₄₇ N₃ O₄); sticky solid; TLC: Rf 0.54 (5%MeOH/CH2Cl₂).

Example 88

[S-[R*,R*,(RS)]]-2-[(2-Hydroxy-1-methyl-ethyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was madein accordance with the procedure of Example 80 (Step 3), except that1-hydroxy-propan-2-one was used instead of 4-fluorobenzaldehyde.

MS: 512 (M+1 for C₃₀ H₄₅ N₃ O₄); TLC: R_(f) 0.39 (5% MeOH/CH₂ Cl₂).

Example 89

[S-(R*,R*)]-4-Methyl-2-[methyl-(1H-pyrrol-2-ylmethyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was madein accordance with the procedure of Example 80 (Step 3), except thatpyrrole-2-carboxaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 533 (M+1 for C₃₂ H₄₄ N₄ O₃); mp 60-62° C.; TLC R_(f) 0.47 (5%MeOH/CH₂ Cl₂).

Example 90

[S-(R*,R*)]-2-(Furan-2-ylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except thatfuran-2-carboxaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 534 (M+1 for C₃₂ H₄₃ N₃ O₄); sticky solid; TLC R_(f) 0.53 (5%MeOH/CH₂ Cl₂).

Example 91

[S-(R*,R*)]-3-(4Benzyloxy-phenyl)-2-[2-(cyclohexylmethyl-amino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester was made in accordance with the procedure ofExample 80 (Step 3), except that[S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester was used instead of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide andcyclohexanecarboxaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 537 (M+1 for C₃₃ H₄₉ N₃ O₃); sticky solid; TLC: Rf 0.46 (5% MeOH/CH₂Cl₂).

Example 92

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-(2-isopropylamino4-methyl-pentanoylamino)-propionicacid tert-butyl ester was made in accordance with the procedure ofExample 80 (Step 3), except that[S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester was used instead of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide,and acetonewas used instead of 4-fluorobenzaldehyde.

MS: 483 (M+1 for C₂₉ H₄₃ N₃ O₃); TLC: R_(f) 0.36 (5% MeOH/CH₂ Cl₂).

Example 93

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-(2-cyclohexylamino-4-methyl-pentanoylamino)-propionicacid tert-butyl ester was made in accordance with the procedure ofExample 80 (Step 3), except that[S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester was used instead of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide, andcyclohexanone was used instead of 4-fluorobenzaldehyde.

MS: 523 (M+1 for C₃₂ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.36 (5%MeOH/CH₂ Cl₂).

Example 94 [S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: (S)-4-Methyl-2-morpholin4-yl-pentanoic acid was synthesizedaccording to the procedure described in Acta PoloniaePharmaceutica--Drug Research, 1994;51:227-229.

Step 2: (S)-4-Methyl-2-morpholin-4-yl-pentanoic acid (0.161 g, 0.800mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere andcooled to 0° C. in an ice-water bath. To this solution were added insuccession N,N-diisopropyl-ethylamine (0.420 mL, 2.41 mmol) and solidO-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate(0.303 g, 0.799 mmol). The resulting reaction mixture was stirred atthat temperature for 30 minutes, solid(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamidemonohydrochloride (0.290 g, 0.800 mmol) was then added. After stirringfor, sequentially, 10 minutes at 0° C. and 45 minutes at ambienttemperature, reaction mixture was mixed with 60 mL of diethyl ether. Theresulting mixture was successively washed with saturated aqueous NaHCO₃solution (2×60 mL), brine (2×60 mL), and was dried over Na₂ SO₄. Thesolution was concentrated in vacuo affording a viscous oil. The crudeproduct was further purified by flash chromatography (60% EtOAc inhexane) and treated with ethereal HCl. Subsequent concentration invacuo, trituration with ether and drying under vacuum provided 0.27 g(62%) of the pure titled compound as a white solid.

MS: 546 (M+for C₃₀ H₄₃ N₃ O₄); mp: 261-263° C.

Example 95

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)2-[4-methyl-2-(3-methyl-butylamino)-pentanoylamino]-propionicacid tert-butyl ester was made in accordance with the procedure ofExample 80 (Step 3), except that[S-(R*,R*)]-2-{2-amino-4-methyl-pentanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester was used instead of[S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide andisovaleraldehyde was used instead of 4-fluorobenzaldehyde.

MS: 511 (M+1 for C₃₁ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.42 (5%MeOH/CH₂ Cl₂).

Example 96[S-(R*,R*)]-({1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-amino)-aceticacid ethyl ester

A mixture of [S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.55 mmol),diisopropyl ethylamine (1.65 mmol), 2-bromoethyl acetate (0.8 mmol), andanhydrous THF (6 mL) was stirred at 25° C. for 6 hours. The precipitatewas filtered off. The reaction mixture was concentrated and purified bycolumn chromatography on silica gel eluting with 10% acetone/methylenechloride to give the titled compound (84% yield).

MS: 540 (M+1 for C₃₁ H₄₅ N₃ O₅); sticky solid; TLC: R_(f) 0.45 (10%acetone/CH₂ Cl₂).

Example 97

[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that3-hydroxybutyraldehyde was used instead of 4-fluorobenzaldehyde.

MS: 511 (M+1 for C₃₁ H₄₇ N₃ O₄); TLC: R_(f) 0.25 (5% MeOH/CH₂ Cl₂).

Example 98

[S-(R*,R*)]-2-[(4-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the procedure of Example 80 (Step 3), except that4-methoxybenzaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 574 (M+1for C₃₅ H₄₇ N₃ O₄); mp 82-84° C.; TLC: R_(f) 0.39 (5%MeOH/CH₂ Cl₂).

Example 99 [S-(R*,R*)]-4-Methyl-2-piperidin-1-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide

Step 1: (S-4-Methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide wassynthesized according to the procedure described in Acta PoloniaePharmaceutica--Drug Research, 1994;51 :227-229, which is herebyincorporated by reference in its entirety.

Step 2: (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamidemonohydrochloride (S)-4-Methyl-2-piperidin-1-yl-pentanoic acidmonohydrobromide (0.493 g, 1.76 mmol) was mixed with dry DMF (4 mL)under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. Tothis mixture were added in succession N,N-diisopropylethylamine (1.23mL, 7.05 mmol ) and solidO-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate(0.667 g, 1.76 mmol ). The resulting reaction mixture was stirred atthat temperature for 30 minutes, solid(S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamidemonohydrochloride (0.639 g, 1.76 mmol) was then added. After stirringfor, sequentially, 10 minutes at 0° C. and 45 minutes at ambienttemperature, reaction mixture was mixed with 60 mL of diethyl ether; theresulting mixture was successively washed with saturated aqueous NaHCO₃solution (2×60 mL), brine (2×60 mL), and was dried over Na₂ SO₄. Thesolution was concentrated in vacuo affording an viscous oil. The crudeproduct was further purified by flash chromatography (40% EtOAc inhexane). Recrystallization from EtOAC/hexanes and subsequent dryingunder vacuum provided 0.4 g (45%) of the pure titled compound as a whitecrystalline solid.

MS: 510 (M+ for C₃₁ H₄₅ N₃ O₃); mp 109-111° C.

Example 100

[S-(R*,R*)]-2-Ethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80, except that N-Boc-L-leucinewas used instead of N-Boc-N-Me-L-leucine in Step 2 (i), and acetaldehydewas used instead of 4-fluorobenzaldehyde in Step 3.

MS: 469 (M+1 for C₂₈ H₄₁ N₃ O₃); sticky solid; TLC: R_(f) 0.3 (EtOAc).

Example 101

[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin-3-ylmethyl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that3-pyridinecarboxaldehyde was used instead of 4-fluorobenzaldehyde.

MS: 545 (M+1 for C₃₃ H₄₄ N₄ O₃); mp 119-120° C.; TLC: R_(f) 0.30 (5%MeOH/CH₂ Cl₂).

Example 102

[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-{2-[methyl-(3-methyl-butyl)-amino]-acetylamino}-propionamidewas made in accordance with the procedure of Example 80, except thatN-Boc-N-methyl-glycine was used instead of N-Boc-N-Me-L-leucine in Step2 (i), and isovaleraldehyde was used instead of 4-fluorobenzaldehyde inStep 3.

MS: 468 (M+1 for C₂₈ H₄₁ N₃ O₃); sticky solid; TLC: R_(f) 0.57 (10%MeOH/CH₂ Cl₂).

Example 103

[S-[R*,R*,(RS)]]-2-(sec-Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide was made inaccordance with the procedure of Example 80 (Step 3), except that2-butanone was used instead of 4-fluorobenzaldehyde.

MS: 511 (M+1 for C₃₁ H₄₇ N₃ O₃); sticky solid, TLC: R_(f) 0.3 (10%MeOH/CH₂ Cl₂).

Example 104

(S)-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-isobutyramidewas made in accordance with the procedure of Example 80, except thatN-Boc-alpha-aminoisobutyric acid was used instead ofN-Boc-N-Me-L-leucine in Step 2 (i), and isovaleraldehyde was usedinstead of 4-fluorobenzaldehyde in Step 3.

MS: 483 (M+1 for C₂₉ H₄₃ N₃ O₃); sticky solid; TLC: R_(f) 0.50 (8%MeOH/CH₂ Cl₂).

Example 105

[S-(R*,R*)]-4-Methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide is made inaccordance with the procedure of Example 80, except that N-Boc-L-leucinewas used instead of N-Boc-N-Me-L-leucine in Step 2 (i) andisovaleraldehyde was used instead of 4-fluorobenzaldehyde in Step 3.

MS: 511 (M+1 for C₃₁ H₄₇ N₃ O₃); sticky solid; TLC: R_(f) 0.18 (1:1hexane/EtOAc).

Example 106 4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

Step 1: The Preparation of(S)-2-Amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide

Step i: To a mixture of BOC-(OBn)tyrosine (5.0 g, 13.5 mmol), DMF (25mL), HBTU (5.15 g, 13.5 mmol), and diisopropylethylamine (8.7 g, 67.5mmol) was added. The resulting solution was treated with2-amino-1-methoxybutane (1.5 g, 14 mmol), and stirred for 2 hours. Thereaction mixture was diluted with 40 mL of ethyl acetate and washed withIN HCl (2×25 mL), saturated NaHCO₃ (2×25 mL) and saturated solution ofbrine (2×25 mL). The organic layer was collected, dried with Na₂ SO₄ andevaporated to dryness. The crude residue was crystallized from petroleumether and toluene to give the title compound (5.98 g, 97%) as acream-colored solid.

APCI-MS 457.2 [M+1 for C₂₇ H₃₈ N₂ O₅ ].

Step ii: A solution of the product from Step i above (1.0 g, 2.8 mmol)was stirred in a solution of TFA/CH₂ Cl₂ =1/1 (10 mL) for 30 minutes andconcentrated to dryness. This crude reaction product was dissolved inCH₂ Cl₂ (30 mL) and washed sequentially with saturated solution ofNaHCO₃ and brine. The CH₂ Cl₂ solution was dried over NaHCO₃ andconcentrated to dryness to give(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.98 g, 98%) as a cream-colored solid.

APCI-MS 357.2 [M+1 for C₂₂ H₃₀ N₂ O₃ ].

Step 2: The Preparation of4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

A solution of(S)-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid(0.13 g, 0.56 mmol) in 10 mL of DMF at 0° C. was treated with HBTU (0.21g, 0.56 mmol) and diisopropylethylamine (0.36 g, 2.80 mmol). Thereaction mixture was stirred for 30 minutes at 0° C. A solution of(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.21 g, 0.56 mmol) in 10 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The reaction mixture was diluted with 20mL of ethyl acetate, washed sequentially with 1N HCl (2×10 mL),saturated aqueous NaHCO₃ (2×10 mL) and brine (2×10 mL). The organiclayer was separated, dried with Na₂ SO₄ and evaporated to dryness. Thecrude residue was purified by chromatography (SiO₂, 1:1 ethylacetate/hexane). The purified product was then dissolved in minimumvolume of diethylether and ethereal solution of HCl was added dropwise.The solid HCl-salt separated out, washed several times with diethyletherto get 0.21 g (62%) of fine cream powder; mp 106-109° C.

Analysis calculated for C₃₃ H₄₉ N₃ O₅ 0.58H₂ O HCl:

C, 64.48; H, 8.39; N, 6.84; H₂ O, 1.70.

Found: C, 64.86; H, 8.51; N, 6.82; H₂ O, 1.80.

Example 107 4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

To a solution of (S)-4-methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoicacid (0.12 g, 0.56 mmol) in 10 mL of DMF was added HBTU (0.21 g, 0.56mmol) and diisopropylethylamine (0.36 g, 2.80 mmol). The mixture wasstirred for 30 minutes at 0° C. A solution of(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.21 g, 0.56 mmol) in 10 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 20 mL ofethylacetate, washed with IN HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The crude waspurified by chromatography (SiO₂ 1:1 hexane/ethyl acetate). The purifiedproduct was then dissolved in minimum volume of diethylether, andethereal solution of HCl was added dropwise. The solid which formed wascollected and washed several times with diethylether to give the titlecompound (0.25 g, 76%) as a cream-colored powder; mp 83-85° C.

Analysis calculated for C₃₃ H₅₁ N₃ O₄ 0.32H₂ O HCl:

C, 66.50; H, 8.90; N, 7.05; H₂ O, 0.97.

Found: C, 66.32; H, 9.01; N, 6.93; H₂ O, 0.99.

Example 108 2-(Isopropyl-methyl-amino)4-methyl-pentanioc acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

A solution of (S)-2-(isopropyl-methyl-amino)-4-methyl-pentanioc acid(0.11 g, 0.56 mmol) in 10 mL of DMF was treated with HBTU (0.21 g, 0.56mmol) and diisopropylethylamine (0.36 g, 2.80 mmol). The mixture wasstirred for 30 minutes at 0° C. A solution of(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.21 g, 0.56 mmol) in 10 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The reaction mixture was diluted with 20mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃(2×10 mL) and saturated solution of brine(2×10 mL). The organic layerwas separated, dried with Na₂ SO₄ and evaporated to dryness. The crudewas purified by chromatography (silica gel, 1:1 hexane/ethyl acetate).The purified product was then dissolved in minimum volume ofdiethylether and an ethereal solution of HCl was added dropwise. Thesolid which formed was washed several times with diethylether. The solidwas dissolved in methanol and treated with activated charcoal, filteredand concentrated. The solid was crystallized from methanol-ether to givethe title compound (0.13 g, 40%) as a white powder mp 101-105° C.

APCI MS 526.3 [M+1 for C₃₁ H₄₇ N₃ O₄ ].

Example 109 2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

To a solution of(S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.33g, 1.12 mmol) in 15 mL of DMF was added HBTU (0.43 g, 1.12 mmol) anddiisopropylethylamine (0.72 g, 5.6 mmol). The mixture was stirred for 30minutes at 0° C. A solution of(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.4 g, 1.12 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 40 mL ofethylacetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The crude waspurified by chromatography (SiO₂, 8:2 hexane/ethyl acetate). Thepurified product was dissolved in minimum volume of diethylether and anethereal solution of HCl was added dropwise. The solid which formed waswashed several times with diethylether to give the title compound (0.28g, 37%) as a cream-colored powder mp 118-120° C.

Analysis calculated for C₃₉ H₅₅ N₃ O₄.HCl:

C, 70.30; H, 8.47; N, 6.31; Cl⁻, 5.32.

Found: C, 69.94; H, 8.46; N, 6.16; Cl⁻, 5.55.

Example 110 2[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide

Step 1: The Preparation of2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic-acid

To a solution of N-methyl leucine (8.0 g, 55.1 mmol) and4-N,N-dimethyl-benzaldehyde (8.4 g, 56.0 mmol) in 80 mL of dry THF wasadded titanium (IV) isopropoxide (15.7 g, 55.1 mmol). The mixture wasstirred at room temperature for 4 hours and was diluted with 20 mL ofabsolute ethanol. NaBH₄ (3.0 g, 80.0 mmol) was added slowly to themixture. The resulting mixture was stirred overnight. The reactionmixture was quenched with 40 mL of water and was filtered to remove aninorganic precipitate. Evaporation of the crude filtrate gave a slurrywhich was dissolved in minimum volume of MeOH and was filtered to removethe last traces of inorganic salt. The filtrated was evaporated todryness, dissolved in minimum volume of 0.1N NaOH and washed withdiethyl ether (4×40 mL) followed by ethyl acetate (2×40 mL). The aqueousphase was acidified to pH 6 with 1N HCl, saturated with NaCl, andextracted with ethyl acetate (6×40 mL). The combined organic extractswere dried over anhydrous Na₂ SO₄ and concentrated to give the product(7.6 g, 49%) as a white solid; mp 176-180° C.

APCI MS 277.3 [M+1 for C₁₆ H₂₆ N₂ O₂ ].

Step 2:2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1 -methoxymethyl-propylcarbamoyl)-ethyl]-amide

A solution of(S)-2-[(4-dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid(0.31 g, 1.12 mmol) in 15 mL of DMF was treated with HBTU (0.425 g, 1.12mmol) and diisopropylethylamine (0.723 g, 5.6 mmol). The reactionmixture was stirred for 30 minutes at 0° C. A solution of(S)-2-amino-3-(4-benzyloxyphenyl)-N-(1-methoxymethyl)propyl propionamide(0.40 g, 1.12 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The reaction mixture was diluted with 40mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃(2×10 mL) and brine (2×10 mL). The organic layer was collected, driedwith Na₂ SO₄ and evaporated to dryness. The crude residue was purifiedby chromatography (silica gel, 6:4 hexane/ethyl acetate). The purifiedproduct was crystallized from diethyl ether and petroleum ether to givethe title compound (0.22 g, 30%) as a white powder; mp 109-112° C.

Analysis calculated for C₃₇ H₅₂ N₄ O₄ :

C, 72.05; H, 8.50; N, 9.08.

Found: C, 71.59; H, 8.44; N, 8.94.

Example 111 4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoicacid[2-(4-benzyoxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide

Step 1: A mixture of BOC-(OBn)tyrosine (5 g, 13.5 mmol), DMF (25 mL),HBTU (5.15 g, 13.5 mmol), and diisopropylethylamine (8.7 g, 67.5 mmol)was treated with 3-1-propyl-piperidinamine, (2.0 g, 14.0 mmol), and wasstirred for 2 hours. The mixture was diluted with 40 mL of ethylacetate, washed with 1N HCl (2×25 mL), saturated NaHCO₃ (2×25 mL), andsaturated solution of brine (2×25 mL). The organic layer was separated,dried with Na₂ SO₄ and evaporated to dryness. The crude residue wascrystallized from petroleum ether and toluene to give the product (5.98g, 89%) as a brown solid.

APCI MS 496.4 [M+1 for C₂₉ H₄₁ N₃ O₄ ].

Step 2:2-Amino-3-(4-benzyloxyphenyl)-N-(l-propyl-piperidin-3-yl)propionamide

A solution of the product from Step 1 above (0.625 g, 1.26 mmol) wasstirred in a solution of TFA/CH₂ Cl₂ 1:1 (10 mL) for 30 minutes andconcentrated to dryness. The crude reaction product was dissolved in CH₂Cl₂ (30 mL) then washed with saturated solution of NaHCO₃ and brine. Theorganic phase was further dried over Na₂ SO₄ and concentrated to drynessto yield the product (0.50 g, 99%) as a brown solid.

APCI MS 396.4 [M+1 or C₂₄ H₃₃ N₃ O₂ ].

Step 3: 4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide

To a solution of the product from Step 2 above (0.3 g, 1.26 mmol) in 15mL of DMF was added HBTU (0.478 g, 1.26 mmol) and diisopropylethylamine(0.815 g, 6.3 mmol). The mixture was stirred for 30 minutes at 0° C. Asolution of(S)-4-methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid(0.50 g, 1.26 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 20 mL ofethyl acetate, washed with 1N HCl (2×0 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wascollected, dried with Na₂ SO₄ and evaporated to dryness. The crude waspurified by chromatography (silica gel, 1:1 hexane/ethyl with 1%methanol and 1% NH₄ OH). The purified product was then dissolved inminimum volume of diethylether and ethereal solution of HCl was addeddropwise. The solid which formed was collected and washed several timeswith diethylether. The solid was dissolved in methanol and treated withactivated charcoal, filtered, and evaporated. The residue wascrystallized from methanol-ether to give the title compound (0.21 g,26%) as a cream-colored powder; mp 135-136° C.

APCI MS 607.4 [M+1 for C₃₆ H₅₄ N₄ O₄ ].

Example 112 4-Methyl-2-[methyl-(3-methyl-butyl-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide

To a solution of (S)-4-methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoicacid (0.27 g, 1.26 mmol) in 15 mL of DMF was added HBTU (0.48 g, 1.26mmol) and diisopropylethylamine (0.82 g, 6.3 mmol). The mixture wasstirred for 30 minutes at 0° C. A solution of2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide(0.50 g, 1.26 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 20 mL ofethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The cruderesidue was purified by chromatography (silica gel, hexane/ethyl acetatecontaining 1% methanol and 1% NH₄ OH). The purified product was thendissolved in minimum volume of diethylether, and an ethereal solution ofHCl was added dropwise. The solid which formed was washed withdiethylether. The solid was dissolved in methanol and treated withactivated charcoal, filtered, and evaporated. The solid was crystallizedfrom methanol-ether to give the title compound (0.31 g, 39%) as a whitepowder; mp 120-124° C.

APCI MS 593.5 [M+1 for C₄₅ H₅₉ N₅ O₄ ].

Example 113 2-(Isopropyl-methyl-amino)-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide:

To a solution of (S)-2-(Isopropyl-methyl-amino)4-methyl-pentanioc acid(0.24 g, 1.26 mmol) in 15 mL of DMF was added HBTU (0.48 g, 1.26 mmol)and diisopropylethylamine (0.82 g, 6.3 mmol). The mixture was stirredfor 30 minutes at 0° C. A solution of2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide(0.50 g, 1.26 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 20 mL ofethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The cruderesidue was purified by chromatography (silica gel, 1:1 hexane/ethylacetate containing 1% methanol and 1% NH₄ OH). The purified product wasthen dissolved in minimum volume of diethylether and ethereal solutionof HCl was added dropwise. The solid which formed was washed severaltimes with diethylether. The solid was dissolved in methanol and treatedwith activated charcoal, filtered, and evaporated. The residue wascrystallized from methanol-ether to give the title compound (0.3 g, 40%)as a white powder; mp 118-122° C.

APCI MS 565.5 [M+1 for C₃₄ H₅₂ N₄ O₃ ].

Example 114 2-[(4-tertButyl-benzyl-)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide

To a solution of(S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.3g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol) anddiisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirred for30 minutes at 0° C. A solution of2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide(0.4 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to warm to room temperature and wasstirred for another 30 minutes. The mixture was diluted with 20 mL ofethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The cruderesidue was purified by chromatography (silica gel, 7:3 hexane/ethylacetate). The purified product was dissolved in minimum volume ofdiethylether and an ethereal solution of HCl was added dropwise. Thesolid which formed was washed several times with diethylether. The solidwas dissolved in methanol and treated with activated charcoal, filtered,and evaporated. The residue was crystallized from methanol-ether to givethe title compound (0.16 g, 23%) as a light yellow powder; mp 160-164°C. (dec).

APCI MS 669.5 M+1 for C₄₂ H₆₀ N₄ O₃.

Example 115 2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide

To a solution of(S)-2-[(4-dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid(0.28 g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol)and diisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirredfor 30 minutes at 0° C. A solution of2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide(0.40 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture.The reaction mixture was allowed to reach the room temperature and wasstirred for another 30 minutes. The mixture was diluted with 40 mL ofethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO₃ (2×10 mL)and saturated solution of brine (2×10 mL). The organic layer wasseparated, dried with Na₂ SO₄ and evaporated to dryness. The cruderesidue was purified by chromatography (silica gel, 6:4 hexane/ethylacetate). The purified product was crystallized from methylene chlorideand petroleum ether to give the title compound (0.34 g, 49%) as a whitepowder; mp 131-133° C.

Analysis calculated for C₄₀ H₅₇ N₅ O₃ :

C, 73.25; H, 8.76; N, 10.68.

Found: C, 73.08; H, 8.85; N, 10.59.

Example 116[S-(R*,R*)]4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide

A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn)-Kaiseroxime resin (Example 57, IIc) in CH₂ Cl₂ was treated with 1.5equivalents of 2-hydroxy-1,1-dimethylethylamine. The suspension wasshaken for 48 hours. After the reaction was completed, additional CH₂Cl₂ and 1 equivalent of polymer supported isocyanate was added. Afterthe suspension was shaken for 48 hours, the resin was filtered off, andthe solvent was evaporated to yield the title product.

APCI MS 538.5 (M+1); HPLC retention time: 26.65 minutes.

Example 117[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide

A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn) -Kaiseroxime resin (Example 57, IIc) in CH₂ Cl₂ was treated with 1.5equivalents of 2-piperdin-1-ylethylamine. The suspension was shaken for48 hours. After the reaction was completed, additional CH₂ Cl₂ and 1equivalent of polymer supported isocyanate was added. After thesuspension was shaken for 48 hours, the resin was filtered off, and thesolvent was evaporated to yield the title product.

APCI MS 579.3 (M+1); HPLC retention time: 19.62 minutes.

Example 118[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide

A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn)-Kaiseroxime resin (Example 57, IIc) in CH₂ Cl₂ was treated with 1.5equivalents of 1-(3-aminopropylamino)-pyrrolidinone. The suspension wasshaken for 48 hours. After the reaction was completed, additional CH₂Cl₂ and 1 equivalent of polymer supported isocyanate was added. Afterthe suspension was shaken for 48 hours, the resin was filtered off, andthe solvent was evaporated to yield the title product.

APCI MS 593.3 (M+1); HPLC retention time: 25.61 minutes.

Example 119

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 2-morpholin4-yl-ethylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 567.3 (M+1); HPLC retention time: 19.00 minutes.

Example 120

[S-(R*,R*)]-4-Methyl-2-morpholin-4yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 2-(2-aminoethyl)pyridine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 559.3 (M+1); HPLC retention time: 19.00 minutes.

Example 121

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except histamine was used instead of N¹ -benzyl-ethane-1,2-diamine.

APCI MS 562.3 (M+1); HPLC retention time: 18.90minutes.

Example 122

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-thiomorpholin-4-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except thiomorpholine was used instead of N¹ -benzyl-ethane-1,2-diamine.

APCI MS 540.2 (M+1); HPLC retention time: 25.65 minutes

Example 123

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 1,1 -dimethyl-2-hydroxy-ethylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 526.3 (M+1); HPLC retention time: 22.65 minutes.

Example 124

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propyl-carbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 2-amino-2-methyl-propane-1,3-diol was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 556.3 (M+1); HPLC retention time: 21.55 minutes.

Example 125

[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except 2-pyrrolidin-1-yl-ethylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 551.3 (M+1); HPLC retention time: 19.34 minutes.

Example 126

[S-(R*,R*)]4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxypiperidinylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 68 (Step 3),except piperidine-4-ol was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 538.3 (M+1); HPLC retention time: 20.96 minutes.

Example 127

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin4-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 2-morpholin-4-yl-ethylamine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 595.3 (M+1); HPLC retention time: 19.40 minutes.

Example 128

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except 2-(2-aminoethyl)pyridine was used instead of N¹-benzyl-ethane-1,2-diamine.

APCI MS 587.3 (M+1); HPLC retention time: 19.36 minutes.

Example 129

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 71 (Step 3),except histamine was used instead of N¹ -benzyl-ethane-1,2-diamine.

APCI MS 590.3 (M+1); HPLC retention time: 19.16 minutes.

Example 130

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidine-1-yl-ethylcarbamoyl]-amide wasprepared in accordance with the procedure of Example 71 (Step 3), except2-pyrrolidine- 1 -yl-ethylamine was used instead of N¹ -benzyl-ethane-1,2-diamine.

APCI MS 579.4 (M+1); HPLC retention time: 19.62 minutes.

Example 131

[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxy-piperinylcarbamoyl]-amide wasprepared in accordance with the procedure of Example 71 (Step 3), except2-4-hydroxypiperidine was used instead of N¹ -benzyl-ethane-1,2-diamine

APCI MS 566.3 (M+1); HPLC retention time: 21.35 minutes.

Example 132

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with Example 57 (Step 3) except[S-(R*,R*)]-2-{2-dimethylamino-4-methyl-penanoylamino}-3-(4-benzyloxy-phenyl)-propionicacid Kaiser oxime resin ester was used instead of IIc (Step 3).

APCI MS 525.4 (M+1): HPLC retention time: 18.83 minutes.

Example 133

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-(2-aminoethyl)pyridinecarbamoyl)-ethyl]-amide was prepared in accordance with the procedure ofExample 132 (Step 3), except 2-(2-aminoethyl)pyridine was used insteadof 2-morpholin-4-yl-ethylamine.

HPLC retention time: 18.81 minutes.

Example 134

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 132 (Step 3),except histamine was used instead of 2-morpholin-4-yl-ethylamine.

APCI MS 520.4 (M+1); HPLC retention time: 18.62 minutes.

Example 135

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(thiomorpholinecarbamoyl)-ethyl]-amide wasprepared in accordance with the procedure of Example 132 (Step 3),except thiomorpholine was used instead of 2-morpholin-4-yl-ethylamine.

APCI MS 498.3 (M+1); HPLC retention time: 25.61 minutes.

Example 136

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-aminopropan-1-ol carbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 133 (Step 3),except 2-aminopropan-1-ol was used instead of2-morpholin-4-yl-ethylamine.

APCI MS 484.4 (M+1); HPLC retention time: 22.62 minutes.

Example 137

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxymethylbutan-1-ol)-ethyl]-amide wasprepared in accordance with the procedure of Example 132 (Step 3),except 2-hydroxymethylbutan-1-ol was used instead of2-morpholin-4-yl-ethylamine.

APCI MS 498.4 (M+1); HPLC retention time: 21.38 minutes.

Example 138

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 132 (Step 3),except 1-methoxymethyl-propylamine was used instead of2-morpholin-4-yl-ethylamine.

APCI MS 498.4 (M+1); HPLC retention time: 24.88 minutes.

Example 139

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amidewas prepared in accordance with the procedure of Example 132 (Step 3),except 2-pyrrolidin-1-yl-ethylamine was used instead of2-morpholin-4-yl-ethylamine.

APCI MS 509.4 (M+1); HPLC retention time: 19.14 minutes.

Example 140

[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amidewas prepared in accordance with the procedure of Example 132 (Step 3),except 2-(2-aminoethylamino)-ethanol was used instead of2-morpholin-4-yl-ethylamine.

APCI MS 499.3 (M+1); HPLC retention time: 18.44 minutes.

Biological Activity

The compounds of the present invention exhibit valuable biologicalproperties because of their ability to block calcium flux through N-typevoltage-gated calcium channels. To measure interaction at the N-typeCa²⁺ channel and calcium flux inhibition, the effects of the compoundsof the present invention were measured in the assays described below.

Measurement of N-type Ca²⁺ Channel Blocking Potencies of Compounds inIMR-32 Cells Using the Fluorescent Ca² + Indicator Indo-1

IMR-32 cells are a human tumoral cell line of neural origin. The IMR-32cell line has been shown to contain both N- and L-type voltage sensitivecalcium channels. Calcium flux into these cells may be induced bystimulation with elevated potassium concentrations. The L-channelcomponent of calcium flux may be blocked by adding 5 μM nitrendipine.The remaining component of calcium entry into the IMR-32 cells is due tocalcium flux through N-type calcium channels. Intracellular calciumconcentrations are measured using the fluorescent calcium indicatorIndo-1. The effect of drug concentration on calcium uptake is studied.

Methods

The IMR-32 cell line was obtained from the American Type CultureCollection (Rockville, Md.). Cells were grown in Eagle's MinimumEssential Medium with Earle's salts supplemented with 10% fetal bovineserum, 2 mM L-Gln and antibiotic/antimycotic mixture (Gibco). Atapproximately 80% confluency, differentiation was induced by theaddition of 1 mM dibutyryl cAMP and 2.5 μM bromodeoxyuridine to themedium. After 7 to 13 days of differentiation, cells were detached using0.5 mM EDTA and loaded with 5 μM Indo-1 acetoxymethyl ester (MolecularProbes, Eugene, Oreg.) at 30° C. for 45 minutes. Loaded cells werewashed twice, resuspended (˜10⁷ cells/mL) in assay buffer (10 mMHEPES/Tris pH 7.4 in Hank's Balanced Salt Solution without bicarbonateor phenol red containing 0.5% bovine serum albumin) and kept on iceuntil use. Fluorescence measurements were carried out in a PhotonTechnology International (PTI, South Brunswick, N.J.) Model RF-F3004spectrofluorometer with dual emission monochromators using excitation at350 nm and emission at 400 and 490 nm. The instrument was equipped witha thermostated cuvette holder with stirring capabilities as well as witha computer-controlled pump which allowed for reagent addition duringmeasurement. Instrument control and data collection was done by PTI'sOSCAR software running on an IBM compatible computer. Differentconcentrations of the test compounds (60 μL in dimethyl sulfoxide) wereadded to 5.94 mL of assay buffer containing approximately 3×10⁶ loadedcells, and 5 μM nitrendipine (in 30 μL EtOH) to block L-type Ca²⁺channels. Samples were incubated for 10 minutes at 30° C. and thenaliquoted into three 10×10 mm disposable acrylic cuvettes. Emissionsignals at 400 and 490 nm were acquired from each cuvette at 30° C. for50 seconds. At 20 seconds after the start of reading, cells weredepolarized by the addition of 160 μL of stimulation solution (1 M KCl,68 mM CaCl₂) to the cuvette via the computer-controlled pump. Ratio ofdual emission signals (400 nm/ 490 nm), which is proportional tointracellular Ca²⁺ concentration, was plotted against time, and thedifference between maximal response after stimulation and basal value(before stimulation) was determined. Values obtained in this way wereplotted as a function of drug concentration. IC₅₀ values of testcompounds were calculated by fitting a four-parameter logistic functionto the data using the least squares method.

In Vivo Biological Protocol

A compound of the present invention was dissolved in water using 10%(weight/volume) Emulphor (GAF Corp., Wayne, N.J.) surfactant. Substanceswere administered by intravenous injection into the retro-orbital venoussinus. All testing was performed 15 minutes or 45 minutes after druginjection. All the male mice, 3-4 weeks old were obtained from JacksonLaboratories Bar Harbour, Me. Immediately before anticonvulsant testing,mice were placed upon a wire mesh, 4 inches square suspended from asteel rod. The square was slowly inverted through 180 degrees and miceobserved for 30 seconds. Any mouse falling from the wire mesh was scoredas ataxia.

Mice were placed into an enclosed acrylic plastic chamber (21 cm height,approximately 30 cm diameter) with a high-frequency speaker (4 cmdiameter) in the center of the top lid. An audio signal generator(Protek model B-810) was used to produce a continuous sinusoidal tonethat was swept linearly in frequency between 8 kHz and 16 kHz once each10 msec. The average sound pressure level (SPL) during stimulation wasapproximately 100 dB at the floor of the chamber. Mice were placedwithin the chamber and allowed to acclimatize for 1 minute. DBA/2 micein the vehicle-treated group responded to the sound stimulus (applieduntil tonic extension occurred, or for a maximum of 60 sec) with acharacteristic seizure sequence consisting of wild running followed byclonic seizures, and later by tonic extension, and finally byrespiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15-20 seconds.

The incidence of all the seizure phases in the drug-treated andvehicle-treated mice was recorded, and the occurrence of tonic seizureswere used for calculatine anticonvulsant ED₅₀ values by probit analysis.Mice were used only once for testing at each time and dose point.Results of this assay are shown below in Table 2.

                  TABLE 1                                                         ______________________________________                                                          IMR 32% of                                                  Example           Blockade @ μM                                            ______________________________________                                         1                IC.sub.50 = 2.3 μM                                        2                92% @ 10, 36% @ 1                                            3                70% @ 10, 21% @ 1                                            4                94% @ 10, 50% @ 1                                            5                81% @ 10, 24% @ 1                                            6                31% @ 10, 16% @ 1                                           7, 34             IC.sub.50 = 0.32 μM                                       8                87% @ 10, 70% @ 1                                            9                89% @ 10, 60% @ 1                                           10                80% @ 10, 61% @ 1                                           11                89% @ 10, 70% @ 1                                           12                88% @ 10, 39% @ 1                                           13, 48            IC.sub.50 = 0.04 μM                                      14                85% @ 10, 80% @ 1                                           15                80% @ 10, 56% @ 1                                           16                66% @ 10, 41% @ 1                                           17                IC.sub.50 = 0.44 μM                                      18                95% @ 10, 52% @ 1                                           19, 56            IC.sub.50 = 0.2 μM                                       20                87% @ 10, 65% @ 1                                           21                IC.sub.50 = 0.88 μM                                      22                87% @ 10, 57% @ 1                                           23                80% @ 3, 53% @ 1                                            24                84% @ 10, 32% @ 1                                           25                IC.sub.50 = 0.67 μM                                      26                IC.sub.50 = 0.6 μM                                       27                IC.sub.50 = 1.3 μM                                       28                IC.sub.50 = 0.5 μM                                       29                IC.sub.50 = 0.6 μM                                       30                IC.sub.50 = 1.2 μM                                       31                IC.sub.50 = 0.32 μM                                      32                IC.sub.50 = 0.25 μM                                      33                95% @ 10, 52% @ 1                                           35                IC.sub.50 = 2.3 μM                                       36                IC.sub.50 = 0.4 μM                                       37                IC.sub.50 = 1.0 μM                                       38                23% @ 1                                                     39                IC.sub.50 = 0.39 μM                                      40                IC.sub.50 = 0.28 μM                                      41                IC.sub.50 = 0.28 μM                                      42                IC.sub.50 = 0.38 μM                                      43                96% @ 10, 51% @ 1                                           44                74% @ 3, 35% @ 0.3                                          45                77% @ 3, 45% @ 0.3                                          46                74% @ 3, 36% @ 0.3                                          47                IC.sub.50 = 0.28 μM                                      49                IC.sub.50 = 0.66 μM                                      50                IC.sub.50 = 0.42 μM                                      51                IC.sub.50 = 1.3 μM                                       52                IC.sub.50 = 0.77 μM                                      53                IC.sub.50 = 0.7 μM                                       54                IC.sub.50 = 0.36 μM                                      55                IC.sub.50 = 0.1 μM                                       57                IC.sub.50 = 2.1 μM                                       58                IC.sub.50 = 1.0 μM                                       59                IC.sub.50 = 1.6 μM                                       60                IC.sub.50 = 0.2 μM                                       61                IC.sub.50 = 0.4 μM                                       62                IC.sub.50 = 1.1 μM                                       63                IC.sub.50 = 0.8 μM                                       64                IC.sub.50 = 2.4 μM                                       65                IC.sub.50 = 1.1 μM                                       66                IC.sub.50 = 1.9 μM                                       67                IC.sub.50 = 0.4 μM                                       68                IC.sub.50 = 1.1 μM                                       69                IC.sub.50 = 1.3 μM                                       70                IC.sub.50 = 2.3 μM                                       71                IC.sub.50 = 0.7 μM                                       72                IC.sub.50 = 1.2 μM                                       73                IC.sub.50 = 2.7 μM                                       74                IC.sub.50 = 2.6 μM                                       75                IC.sub.50 = 2.4 μM                                       76                IC.sub.50 = 0.6 μM                                       77                IC.sub.50 = 2.6 μM                                       78                IC.sub.50 = 1.6 μM                                       79                IC.sub.50 = 2.1 μM                                       80                IC.sub.50 = 0.3 μM                                       81                IC.sub.50 = 0.16 μM                                      82                IC.sub.50 = 1.3 μM                                       83                IC.sub.50 = 1.3 μM                                       84                IC.sub.50 = 0.37 μM                                      85                IC.sub.50 = 0.32 μM                                      86                IC.sub.50 = 2.8 μM                                       87                IC.sub.50 = 3.1 μM                                       88                30% blockade @ 1 μM                                      89                IC.sub.50 = 1.0 μM                                       90                IC.sub.50 = 0.9 μM                                       91                IC.sub.50 = 0.3 μM                                       92                IC.sub.50 = 0.8 μM                                       93                IC.sub.50 = 0.2 μM                                       94                24% @ 1 μM                                               95                IC.sub.50 = 0.46 μM                                      96                IC.sub.50 = 4.4 μM                                       97                IC.sub.50 = 2.2 μM                                       98                IC.sub.50 = 0.4 μM                                       99                IC.sub.50 = 1.4 μM                                       100               IC.sub.50 = 2.0 μM                                       101               26% @ 1 μM                                               102               IC.sub.50 = 1.6 μM                                       103               IC.sub.50 = 1.5 μM                                       104               IC.sub.50 = 1.3 μM                                       105               IC.sub.30 = 0.24 μM                                      103               100%(10 mg/kg)                                              104               IC.sub.50 = 1.3 μM                                       105               IC.sub.50 = 0.24 μM                                      116               1.4 μM                                                   117               0.64 μM                                                  118               1.9 μM                                                   119               18 μM                                                    120               6 μM                                                     121               14 μM                                                    122               3.1 μM                                                   123               13 μM                                                    124               7.2 μM                                                   125               9.7 μM                                                   126               6.4 μM                                                   127               7.5 μM                                                   128               3.9 μM                                                   129               6.3 μM                                                   130               6.5 μM                                                   131               10 μM                                                    132               12 μM                                                    133               5.9 μM                                                   134               1.6 μM                                                   135               1.4 μM                                                   136               3.6 μM                                                   137               6.2 μM                                                   138               3.0 μM                                                   139               38.8 μM                                                  140               5.1 μM                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        In Vivo anticonvulsory Activity in Mico                                       Example    DBA/2 mice                                                         Number     % Protection dose @ 30 mg/kg                                       ______________________________________                                        7          100%                                                               13         60%                                                                25         100%                                                               31         100%                                                               47         100%                                                               84         100%           (10 mg/kg)                                          90         60%            (30 mg/kg)                                          92         100%           (30 mg/kg)                                          93         80%            (30 mg/kg)                                          97         40%            (30 mg/kg)                                          103        100%           (10 mg/kg)                                          ______________________________________                                    

What is claimed is:
 1. A compound having Formula I ##STR37## wherein: *is a first chiral center;@ is a second chiral center; R¹ and R²independently are:(a) C₁ -C₈ alkyl, unsubstituted or substituted withone or two of halo, hydroxy, amino, alkylamino or dialkylamino; (b) C₂-C₈ alkenyl, unsubstituted or substituted with one or two of halo,hydroxy, amino, C₁ -C₄ -alkylamino or di(C1-C4)-alkylamino; (c)(CH₂)_(n) --C₃ -C₇ cycloalkenyl, unsubstituted or substituted by one ortwo of halo, hydroxy, C₁ -C₄ alkyl, amino, C₁ -C₄ -alkylamino or di(C₁-C₄)-alkylamino; (d) (CH₂)_(n) --C₃ -C₇ cycloalkyl, unsubstituted orsubstituted with one or two of halo hydroxy, C₁ -C₄ alkyl, amino, C₁ -C₄-alkylamino or di(C₁ -C₄)-alkylamino; (e) (CH₂)_(n) phenyl,unsubstituted or substituted with one or two of C₁ -C₄ alkyl, benzyloxy,amino, C₁ -C₄ alkylamino, di(C₁ -C₄)-alkylamino, halo, C₁ -C₄ alkoxy;(f) (CH₂)_(n) -pyridyl ##STR38## R³, R⁵ and R⁶ independently arehydrogen or C₁ -C₈ alkyl; R⁴ is:(a) C₁ -C₈ alkyl; (b) (CH₂)_(n) --C₃ -C₇cycloalkyl, unsubstituted or substituted with one or two of halo,hydroxy, C₁ -C₄ alkyl, amino, C₁ -C₄ alkylamino or di-C₁ -C₄ alkylamino;or (c) (CH₂)_(n) phenyl; X is:(a) --NHR³ ; (b) --NR³ R⁵ ; (c)--NH(CH₂)_(n) NR³ R⁵ ; (d) --NH(CH₂)_(n) NH(CH₂)_(n) phenyl; (e) --NH(CH₂)_(n) NH(CH₂)_(n) --OH; ##STR39## n is 0 to 5; and thepharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R¹ is methyl.
 3. A compound according to claim 1 wherein##STR40## or --O-tert-butyl.
 4. A compound according to claim 1whereinR² is C₁ -C₈ alkyl, substituted cyclohexyl, cyclohexyl,cyclohexenyl, --CH₂ -phenyl, --CH₂ -substituted phenyl, --CH₂-cyclohexyl, alkenyl, ##STR41##
 5. A compound according to claim 1wherein R² is C₁ -C₈ alkyl, cyclohexyl, substituted cyclohexyl, --CH₂-phenyl, or CH₂ -substituted phenyl.
 6. A compound according to claim 1wherein
 7. A compound according to claim 1 wherein R² is C₁ -C₈ alkenyl.8. A compound according to claim 1 wherein R¹ is methyl;R² is C₁ -C₈alkyl, substituted cyclohexyl, cyclohexyl, cyclohexenyl, --CH₂ -phenyl,--CH₂ -substituted phenyl, --CH₂ -cyclohexyl, C₁ -C₈ alkenyl, --CH₂-pyridyl, ##STR42## R⁴ is isobutyl; ##STR43##
 9. A compound according toclaim 1 wherein Y is --O--CH₂ -- or ##STR44## Z is phenyl; ##STR45## R⁴and R⁵ are hydrogen; R³ is isobutyl;R¹ is methyl; and R² is C₁ -C₈alkyl, --(CH₂)_(n) substituted phenyl, or cyclohexyl.
 10. A compoundselected from:2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-benzyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amide2-Dimethylamino-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin- 1-yl)-2-oxo-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-yl-carbamoyl)-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbonyl)-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-piperidin-4-ylcarbamoyl)-ethyl]-amide;2-(Cyclohexylmethyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-but-2-enylamino)-pentanoylamino]-propionicacid tert-butyl ester;3-(4-Benzyloxy-phenyl)-2-[2-(4-tert-butyl-benzylamino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester;2-(2-Benzylamino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionicacid tert-butyl ester;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-methylamino-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(3,3-Dimethyl-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-Diethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl-]-amide;2-[(4-tert-Butyl-cyclohexyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(4-methyl-cyclohexyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbarnoyl-ethyl]-amide;2-(Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Isobutyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-methylamino-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;3-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[ethyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-butyric acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohex-2-enyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohex-2-enylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(4-tert-Butyl-benzylamino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-(Benzyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzylamino-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide; and2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.
 11. Acompound selectedfrom:2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(2-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(2-Hydroxycyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(Isoprop-2-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(N-methyl-piperidin-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(N-methyl-piperidin-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(Pyran-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(Pyran-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Bromo-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(3-Chloro-benzyl)-methyl-amino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Hydroxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-(piperidine-1-carbamoyl-ethyl]-amide;2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(2-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(2-Hydroxycyclohexyl-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-(Isoprop-2-yl)-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[N-methyl-piperidin-4-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(N-methyl-piperidin-4-yl)-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(Pyran-4-yl)-methyl-amino]4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(Pyran-4-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl-1-(piperidine-1-carbamoyl-ethyl]-amide;2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(piperidine-1-carbamoyl-ethyl]-amide;2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Bromo-benzyl)-methyl-amino]4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Hydroxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Ethoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(3-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(2-Methoxybenzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-[(4-Pyridyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(2-Hydroxycyclohexyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;4-Methyl-2-[methyl-(N,N-dimethyl-3-amino-propyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;2-(Cyclohexyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl]-2-oxo-ethyl]-amide;2-[(Isoprop-2-yl)-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-[(Isoprop-2-yl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-Pyrrolidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;2-Piperidine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;and 2-Hexamethyleneimine-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide.12. A pharmaceutical composition comprising a compound of claim
 1. 13. Amethod of treating epilepsy, the method comprising administering to apatient having epilepsy a therapeutically effective amount of a compoundof claim
 1. 14. A method of treating pain, the method comprisingadministering to a patient having pain a therapeutically effectiveamount of a compound of claim
 1. 15. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R* )]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide; [S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;and [S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amide.16. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetahydro-pyran-4-ylamino)-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-thiomorpholin-4-yl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;and [S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-benzyl-pyrrolidin-3-ylcarbamoyl)-ethyl]-amide.17. Thecompounds:[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid[1-(4-benzyloxy-benzyl)-2-oxo-2-piperidin-1-yl-ethyl]-amide;[S-(R*,R*)]-2-[(4-Fluoro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(4-Bromo-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(4-Hydroxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin-4-ylmethyl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,S*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoylamino]-propionicacid tert-butyl ester; and[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.
 18. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-[R*,R*,(RS)]]-2-[(2-Hydroxy-1-methyl-ethyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(1H-pyrrol-2-ylmethyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-(Furan-2-ylmethyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[2-(cyclohexylmethyl-amino)-4-methyl-pentanoylamino]-propionicacid tert-butyl ester;[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-(2-isopropylamino-4-methyl-pentanoylamino)-propionicacid tert-butyl ester;[S-(R*,R*)]-3-3-(4-Benzyloxy-phenyl)-2-(2-cyclohexylamino-4-methyl-pentanoylamino)-propionicacid tert-butyl ester; [S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-2-[4-methyl-2-(3-methyl-butylamino)-pentanoylamino]-propionicacid tert-butyl ester; and[S-(R*,R*)]-({1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-amino)-aceticacid ethyl ester.
 19. Thecompounds:[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(4-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-piperidin-1-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-Ethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(methyl-pyridin-3-ylmethyl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-{2-[methyl-(3-methyl-butyl)-amino]-acetylamino}-propionamide;[S-[R*,R*,(RS)]]-2-(sec-Butyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;(S)-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-isobutyramide;[S-(R*,R*)]-4-Methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide; and4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide.20. The compounds:4-Methyl-2-[methyl-(3-methylbutyl)-amino]3-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;2-(Isopropyl-methyl-amino)-4-methyl-pentanioc acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;2-(Isopropyl-methyl-amino)-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;2-[(4-tertButyl-benzyl-)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;[S,(R*,R*)]-4-Methyl-2-piperidin-1-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide; and[S,(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amidemonohydrochloride.
 21. Thecompounds:[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;[S-(R*,R*)]-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid{1-tert-butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-phenyl]-ethyl}-amide;[S-(R*,R*)]-2-[(3-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(2-Methoxy-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(4-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide;[S-(R*,R*)]-2-[(3-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbarnoyl-ethyl]-amide;[S-(R*,R*)]-2-[(2-Chloro-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide; and[S-(R*,R*)]-4-Methyl-2-[methyl-(4-methylsulfanyl-benzyl)-amino]-pentanoicacid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.
 22. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide; [S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid{2-(4-benzyloxy-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-ethyl}-amide;[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide;and[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-piperidin-1-yl-ethylcarbamoyl)-ethyl]-amide.23. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(4-benzyloxy-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;and[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide.24. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;[S-(R*,R*)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid[1-(2-benzylamino-ethylcarbamoyl)-2-(4-benzyloxy-phenyl)-ethyl]-amide;[S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;and [S-(R*,R*)]-4-Methyl-2-methyl-(3-methyl-butyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide.25. Thecompounds:[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;and [S-(R*,R*)]-2-[(3-Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide.26. Thecompounds:[S-(R*,R*)]-2-(Isopropyl-methyl-amino)-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;2-[(3 -Hydroxy-butyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;and 2-[(3-Hydroxy-butyl)-methyl-amino]4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide.27. Thecompounds:[S-(R*,R*)]-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-phenethyl-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclohexyl-ethyl)-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;[S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclopentyl-ethyl)-phenyl)-1-tert-butylcarbamoyl-ethyl] amide;and [S-(R*,R*)]-4-methyl-2-(3-methyl-butylamino)-pentanoic acid[2-(4-(2-cyclohexyl-ethyl)-phenyl)-1-(1,1-bis-hydroxymethyl-propylcarbamoyl)-ethyl]amide.
 28. Thecompounds:4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoicacid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-(3-methylbutyl)-amino]-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;2-(Isopropyl-methyl-amino)-4-methyl-pentanioc acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-tetrahydropyran-4-yl)-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;4-Methyl-2-[methyl-(3-methyl-butyl-amino]-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;2-(Isopropyl-methyl-amino)-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;2-[(4-tertButyl-benzyl-)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide;and 2-[(4-Dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid[2-(4-benzyloxyphenyl)-1-(1-propyl-piperidin-3-ylcarbamoyl)-ethyl]-amide.29. The compounds:[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-thiomorpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-hydroxy-1,1-dimethyl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1,1-bis-hydroxymethyl-propyl-carbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-morpholin-4-yl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxypiperidinylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(-(2-pyridin-2-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidine-1-yl-ethylcarbamoyl]-amide;[S-(R*,R*)]-4-Methyl-2-(tetrahydropyran-4-yl-amino)-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(4-hydroxy-piperinylcarbamoyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-(2-aminoethyl)pyridinecarbamoyl)-ethyl]-amide; [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoicacid[2-(4-benzyloxy-phenyl)-1-(3-imidazol-1-yl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(thiomorpholinecarbamol)-ethyl)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-aminopropan-1-ol carbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2 -hydroxymethylbutan-1-ol)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(1-methoxymethyl-propylcarbamoyl)-ethyl]-amide;[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid[2-(4-benzyloxy-phenyl)-1-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-amide;and [S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid{2-(4-benzyloxy-phenyl)-1-[2-(2-hydroxy-ethylamino)-ethylcarbamoyl]-ethyl}-amide.